Abstract:

The present invention relates to an amide derivative of the formula (1),
having a C5a receptor antagonistic action
##STR00001##
wherein each symbol is as defined in the specification.
The above-mentioned amide derivative, an optically active form thereof and
a pharmaceutically acceptable salt thereof are promising as an agent for
the treatment or prophylaxis of diseases or syndromes caused by
inflammation caused by C5a [e.g., autoimmune diseases such as rheumatism,
systemic lupus erythematosus and the like, sepsis, adult respiratory
distress syndrome, chronic obstructive pulmonary disease, allergic
diseases such as asthma and the like, atherosclerosis, cardiac
infarction, brain infarction, psoriasis, Alzheimer's disease and serious
organ injury (e.g., pneumonia, nephritis, hepatitis and pancreatitis and
the like) due to activation of leukocytes caused by ischemia reperfusion,
trauma, burn, surgical invasion and the like]. Moreover, they are useful
as a therapeutic or prophylactic agent for the infectious diseases caused
by bacteria and virus that invade via a C5a receptor.

Claims:

1. An amide derivative represented by the formula (1) ##STR00455##
whereinR1, R23 and R3 are the same or different and each
is hydrogen atom, alkyl group optionally having substituents, alkenyl
group optionally having substituents, alkynyl group optionally having
substituents, cycloalkyl group optionally having substituents, aryl group
optionally having substituents, heteroaryl group optionally having
substituents, arylalkyl group optionally having substituents,
heteroarylalkyl group optionally having substituents, alkoxy group
optionally having substituents, aryloxy group, arylalkyloxy group,
acyloxy group optionally having substituents, halogen atom, hydroxyl
group, nitro group, cyano group, acyl group, mercapto group, alkylthio
group, alkylsulfonyl group, amino group, alkylamino group, dialkylamino
group, cyclic amino group, carbamoyl group optionally having
substituents, alkoxycarbonyl group, carboxyl group, acylamino group,
sulfamoyl group optionally having substituents or haloalkyl group, or any
two of R1, R2 and R3 in combination with the adjacent
carbon atom may form a ring,a, b, c, d and eare each carbon atom, or 1 or
2 of a, b, c, d and e is(are) nitrogen atom(s) (provided that the
nitrogen atom here may be bonded to oxygen atom to form amine oxide) and
the rest are carbon atoms,R4, R5 and R6 are the same or
different and each is hydrogen atom, alkyl group optionally having
substituents, alkenyl group optionally having substituents, alkynyl group
optionally having substituents, cycloalkyl group optionally having
substituents, aryl group optionally having substituents, heteroaryl group
optionally having substituents, arylalkyl group optionally having
substituents, heteroarylalkyl group optionally having substituents,
alkoxy group optionally having substituents, aryloxy group, arylalkyloxy
group, acyloxy group optionally having substituents, halogen atom,
hydroxyl group, nitro group, cyano group, acyl group, mercapto group,
alkylthio group, alkylsulfonyl group, amino group, alkylamino group,
dialkylamino group, cyclic amino group, carbamoyl group optionally having
substituents, alkoxycarbonyl group, carboxyl group, acylamino group,
sulfamoyl group optionally having substituents, haloalkyl group or
haloalkyloxy group,A is hydrogen atom, cycloalkyl group optionally having
substituents, aryl group optionally having substituents, heteroaryl group
optionally having substituents or cyclic amino group optionally having
substituents,W1 and W2are the same or different and each is a bond or
alkylene(Cn) optionally having substituents wherein n is an integer
of 1 to 3,X is oxygen atom or sulfur atom,Y is a bond, oxygen atom,
--CO--, --N(R7)-- wherein R7 is hydrogen atom or alkyl group
optionally having substituents, --SOm-- wherein m is an integer of 0
to 2, --CON(R8)-- wherein R8 is hydrogen atom or alkyl group
optionally having substituents or --N(R9)CO-- wherein R9 is
hydrogen atom or alkyl group optionally having substituents), andZ is a
bond or alkylene group optionally having substituents,an optically active
form thereof or pharmaceutically acceptable salt thereof.

2. The amide derivative of claim 1, wherein, in the formula (I), R1,
R2 and R3 are the same or different and each is hydrogen atom,
alkyl group optionally having substituents, alkenyl group optionally
having substituents, alkynyl group optionally having substituents,
cycloalkyl group, alkoxy group optionally having substituents, acyloxy
group optionally having substituents, halogen atom, hydroxyl group, nitro
group, cyano group, acyl group, mercapto group, alkylthio group,
alkylsulfonyl group, amino group, alkylamino group, dialkylamino group,
cyclic amino group, carbamoyl group, alkoxycarbonyl group, carboxyl
group, tetrazolyl group, oxadiazolyl group, sulfamoyl group or haloalkyl
group,a, b, c, d and e are each carbon atom, or 1 or 2 of a, b, c, d and
e is(are) nitrogen atom(s) and the rest are carbon atoms,R4, R5
and R6 are the same or different and each is hydrogen atom, alkyl
group optionally having substituents, alkenyl group optionally having
substituents, alkynyl group optionally having substituents, cycloalkyl
group, alkoxy group optionally having substituents, acyloxy group
optionally having substituents, halogen atom, hydroxyl group, nitro
group, cyano group, acyl group, mercapto group, alkylthio group,
alkylsulfonyl group, amino group, alkylamino group, dialkylamino group,
cyclic amino group, carbamoyl group, alkoxycarbonyl group, carboxyl
group, tetrazolyl group, oxadiazolyl group, sulfamoyl group or haloalkyl
group,A is hydrogen atom, cycloalkyl group, aryl group optionally having
substituents, heteroaryl group optionally having substituents or cyclic
amino group,W1 and W2 are the same or different and each is a
bond or alkylene(Cn) optionally having substituents wherein n is an
integer of 1 to 3,X is oxygen atom or sulfur atom,Y is a bond, oxygen
atom, --CO--, --N(R7)-- wherein R7 is hydrogen atom or alkyl
group optionally having substituents, --SOm-- wherein m is an
integer of 0 to 2, --CON(R8)-- wherein R8 is hydrogen atom or
alkyl group optionally having substituents or --N(R9)CO-- wherein
R9 is hydrogen atom or alkyl group optionally having substituents,
andZ is a bond or alkylene group optionally having substituents, an
optically active form thereof or a pharmaceutically acceptable salt
thereof.

3. The amide derivative of claim 2, wherein a, b, c, d and e in the
formula (1) are all carbon atoms,an optically active form thereof or a
pharmaceutically acceptable salt thereof.

4. The amide derivative of claim 1, wherein R1, R2 and R3
in the formula (1) are the same or different and each is hydrogen atom,
alkyl group having 2 to 4 carbon atoms or alkoxy group,an optically
active form thereof or a pharmaceutically acceptable salt thereof.

5. The amide derivative of claim 1, wherein R1, R2 and R3
in the formula (1) are the same or different and each is hydrogen atom,
alkyl group having 2 to 4 carbon atoms or alkoxy group having 2 to 4
carbon atoms,an optically active form thereof or a pharmaceutically
acceptable salt thereof.

6. The amide derivative of claim 1, wherein R1, R2 and R3
in the formula (1) are the same or different and each is hydrogen atom,
alkyl group having 2 to 4 carbon atoms or methoxy group,an optically
active form thereof or a pharmaceutically acceptable salt thereof.

7. The amide derivative of claim 1, wherein R4, R5 and R6
in the formula (1) are the same or different and each is hydrogen atom,
alkyl group optionally having substituents, alkoxy group optionally
having substituents, acyloxy group optionally having substituents,
halogen atom, hydroxyl group, amino group, alkylamino group, dialkylamino
group, cyclic amino group, carboxyl group, haloalkyl group or
haloalkyloxy group,an optically active form thereof or a pharmaceutically
acceptable salt thereof.

8. The amide derivative of claim 1, wherein R4, R5 and R6
in the formula (1) are the same or different and each is hydrogen atom,
alkyl group optionally having substituents, alkoxy group optionally
having substituents, acyloxy group optionally having substituents,
halogen atom, hydroxyl group, amino group, alkylamino group, dialkylamino
group, cyclic amino group, carboxyl group or haloalkyl group,an optically
active form thereof or a pharmaceutically acceptable salt thereof.

9. The amide derivative of claim 1, wherein Z of the formula (1) is
--CH2--,an optically active form thereof or a pharmaceutically
acceptable salt thereof.

10. The amide derivative of claim 1, wherein A of the formula (1) is aryl
group optionally having substituents or heteroaryl group optionally
having substituents,an optically active form thereof or a
pharmaceutically acceptable salt thereof.

11. The amide derivative of claim 1, wherein A of the formula (1) is
phenyl group optionally having substituents, pyridyl group optionally
having substituents, pyrazolyl group optionally having substituents,
thiazolyl group optionally having substituents, oxazolyl group optionally
having substituents or thienyl group optionally having substituents,an
optically active form thereof or a pharmaceutically acceptable salt
thereof.

13. The amide derivative of claim 1, wherein X of the formula (1) is
oxygen atom,an optically active form thereof or a pharmaceutically
acceptable salt thereof.

14. The amide derivative of claim 1, wherein --W1--Y--W2-- of
the formula (1) is --(CH2)2--, --(CH2)3-- or
--(CH2)2O--,an optically active form thereof or a
pharmaceutically acceptable salt thereof.

15. The amide derivative of claim 1, wherein R1, R2 and R3
of the formula (I) are the same or different and each is hydrogen atom,
alkyl group having 2 to 4 carbon atoms or alkoxy group having 2 to 4
carbon atoms,a, b, c, d and e are each carbon atom, or either b or d is
nitrogen atom and the rest are carbon atoms,R4, R5 and R6
are the same or different and each is hydrogen atom, methoxy group,
halogen atom or hydroxyl group,Z is --CH2--,A is phenyl group
optionally having substituents or nitrogen-containing heterocyclic group
selected from the group consisting of the following formulas (Aa')-(Ae')
##STR00457## wherein R10a, R11 and R12 are the same or
different and each is hydrogen atom, alkyl group optionally having
substituents, cycloalkyl group optionally having substituents, aryl group
optionally having substituents, heteroaryl group optionally having
substituents, arylalkyl group optionally having substituents,
heteroarylalkyl group optionally having substituents, alkoxy group
optionally having substituents, aryloxy group, arylalkyloxy group,
halogen atom, hydroxyl group, nitro group, cyano group, alkylthio group,
amino group, alkylamino group, dialkylamino group, cyclic amino group,
haloalkyl group, haloalkyloxy group,
R13O(CH2)jO(CH2)kO(CH2)lO-- wherein j,
k and l are each independently an integer of 2 to 10, R13 is
hydrogen atom, alkyl group optionally having substituents, cycloalkyl
group optionally having substituents, aryl group optionally having
substituents, heteroaryl group optionally having substituents, arylalkyl
group optionally having substituents, heteroarylalkyl group optionally
having substituents or haloalkyl group, or
R13O(CH2)jO(CH2)kO-- wherein j, k and R13
are as defined above, R10b is hydrogen atom, alkyl group optionally
having substituents, cycloalkyl group optionally having substituents,
aryl group optionally having substituents, heteroaryl group optionally
having substituents, arylalkyl group optionally having substituents,
heteroarylalkyl group optionally having substituents, haloalkyl group,
haloalkyloxy group,
R13O(CH2)jO(CH2)kO(CH2)l-- wherein j,
k, l and R13 are as defined above, or
R13O(CH2)jO(CH2)k-- wherein j, k and R13
are as defined above,X is oxygen atom, and--W1--Y--W2-- is
--(CH2)2-- or --(CH2)3--,an optically active form
thereof or a pharmaceutically acceptable salt thereof.

19. A pharmaceutical composition comprising the amide derivative of any of
claims 1 to 18, an optically active form thereof or a pharmaceutically
acceptable salt thereof, and a pharmaceutically acceptable additive.

20. A prophylactic or therapeutic drug of a disease, in which C5a is
involved, which comprises the amide derivative of any of claims 1 to 18,
an optically active form thereof or a pharmaceutically acceptable salt
thereof as an active ingredient.

23. A C5a receptor antagonist comprising the amide derivative of any of
claims 1 to 18, an optionally active form thereof or a pharmaceutically
acceptable salt thereof as an active ingredient.

24. The C5a receptor antagonist of claim 23, which is a prophylactic or
therapeutic drug of an infectious disease caused by bacteria or virus
that invades via the C5a receptor.

25. The C5a receptor antagonist of claim 23, which is used in combination
with an agent for the prophylaxis or treatment of an autoimmune disease,
sepsis, adult respiratory distress syndrome, chronic obstructive
pulmonary disease, an allergic disease, atherosclerosis, cardiac
infarction, brain infarction, psoriasis, Alzheimer's disease, or serious
organ injury due to activation of leukocytes caused by ischemia
reperfusion, trauma, burn or surgical invasion.

26. A combination drug with an agent for the prophylaxis or treatment of
an autoimmune disease, sepsis, adult respiratory distress syndrome,
chronic obstructive pulmonary disease, an allergic disease,
atherosclerosis, cardiac infarction, brain infarction, psoriasis,
Alzheimer's disease, or serious organ injury due to activation of
leukocytes caused by ischemia reperfusion, trauma, burn or surgical
invasion, which comprises the amide derivative of any of claims 1 to 18,
an optionally active form thereof or a pharmaceutically acceptable salt
thereof as an active ingredient.

Description:

TECHNICAL FIELD

[0001]The present invention relates to an amide derivative showing a C5a
receptor antagonistic action and useful for the prophylaxis or treatment
of autoimmune diseases such as rheumatism, systemic lupus erythematosus
and the like, sepsis, adult respiratory distress syndrome, chronic
obstructive pulmonary disease, allergic diseases such as asthma and the
like, atherosclerosis, cardiac infarction, brain infarction, psoriasis,
Alzheimer's disease or serious organ injury (e.g., pneumonia, nephritis,
hepatitis and pancreatitis and the like) due to activation of leukocytes
caused by ischemia reperfusion, trauma, burn, surgical invasion and the
like, an optically active form thereof a pharmaceutically acceptable salt
thereof and pharmaceutical use thereof.

BACKGROUND ART

[0002]When the complement system is activated, the protein of the
complement system is enzymolysed and fragments having various
physiological activities are produced. One of the fragments, complement
component C5a, is a glycoprotein having a molecular weight of about
11,000, consists of 74 amino acids and has a strong inflammation inducing
action. C5a has a broad range of actions such as smooth muscle
contraction, promotion of blood vessel permeability, migration of
leukocyte, degranulation of leukocyte, production of reactive oxygen
species, reinforcement of antibody production, induction of production of
cytokine, TNF (tumor necrosis factor) and leukotriene, and the like, and
is said to be a causative substance of diseases such as autoimmune
diseases (e.g., rheumatism and systemic lupus erythematosus and the
like), sepsis, adult respiratory distress syndrome, chronic obstructive
pulmonary disease, allergic diseases (e.g., asthma and the like),
atherosclerosis, cardiac infarction, brain infarction, psoriasis,
Alzheimer's disease, serious organ injuries (e.g., pneumonia, nephritis,
hepatitis, pancreatitis and the like) due to activation of leukocytes
caused by ischemia reperfusion, trauma, burn, surgical invasion and the
like, and the like [Annu. Rev. Immunol., vol. 12, pp. 775-808 (1994),
Immunopharmacology, vol. 38, pp. 3-15 (1997), Curr. Pharm. Des., vol. 5,
pp. 737-755 (1999) and IDrugs, vol. 2, pp. 686-693 (1999)].

[0003]Accordingly, a non-peptide small molecular compound having a C5a
receptor antagonistic action is expected as a novel non-steroid type
antiinflammatory drug. In addition, it can be expected as a prophylactic
or therapeutic drug of infectious diseases caused by bacteria or virus
that invades via a C5a receptor.

[0004]As regards the C5a antagonist, for example, the following patent
applications have been published. JP-A-10-182648 discloses TAN-2474
related compounds having a C5a antagonistic action. In addition, the
specification of WO94/07815 discloses peptide derivatives having a C5a
receptor antagonistic action, the specification of WO99/00406 discloses
cyclic peptide derivatives having a C5a receptor antagonistic action.

[0005]Heretofore, however, a pharmaceutical drug, that prevents or treats
diseases or syndromes due to the inflammation caused by C5a by inhibiting
the action of C5a, has not been developed.

DISCLOSURE OF THE INVENTION

[0006]In view of the above-mentioned situation, the present inventors have
conducted intensive studies with the aim of finding a non-peptide
compound having a C5a receptor antagonistic action. As a result, they
have found that an amide derivative according to the present invention
shows a C5a receptor antagonistic action, which resulted in the
completion of the present invention.

[0007]Accordingly, the present invention provides the following.

1. An amide derivative represented by the formula (1)

##STR00002##

wherein [0008]R1, R2 and R3[0009]are the same or
different and each is hydrogen atom, alkyl group optionally having
substituents, alkenyl group optionally having substituents, alkynyl group
optionally having substituents, cycloalkyl group optionally having
substituents, aryl group optionally having substituents, heteroaryl group
optionally having substituents, arylalkyl group optionally having
substituents, heteroarylalkyl group optionally having substituents,
alkoxy group optionally having substituents, aryloxy group, arylalkyloxy
group, acyloxy group optionally having substituents, halogen atom,
hydroxyl group, nitro group, cyano group, acyl group, mercapto group,
alkylthio group, alkylsulfonyl group, amino group, alkylamino group,
dialkylamino group, cyclic amino group, carbamoyl group optionally having
substituents, alkoxycarbonyl group, carboxyl group, acylamino group,
sulfamoyl group optionally having substituents or haloalkyl group, or any
two of R1, R2 and R3 in combination with the adjacent
carbon atom may form a ring, [0010]a, b, c, d and e [0011]are each
carbon atom, or 1 or 2 of a, b, c, d and e is(are) nitrogen atom(s)
(provided that the nitrogen atom here may be bonded to oxygen atom to
form amine oxide) and the rest are carbon atoms, [0012]R4, R5
and R6[0013]are the same or different and each is hydrogen atom,
alkyl group optionally having substituents, alkenyl group optionally
having substituents, alkynyl group optionally having substituents,
cycloalkyl group optionally having substituents, aryl group optionally
having substituents, heteroaryl group optionally having substituents,
arylalkyl group optionally having substituents, heteroarylalkyl group
optionally having substituents, alkoxy group optionally having
substituents, aryloxy group, arylalkyloxy group, acyloxy group optionally
having substituents, halogen atom, hydroxyl group, nitro group, cyano
group, acyl group, mercapto group, alkylthio group, alkylsulfonyl group,
amino group, alkylamino group, dialkylamino group, cyclic amino group,
carbamoyl group optionally having substituents, alkoxycarbonyl group,
carboxyl group, acylamino group, sulfamoyl group optionally having
substituents, haloalkyl group or haloalkyloxy group, [0014]A is
hydrogen atom, cycloalkyl group optionally having substituents, aryl
group optionally having substituents, heteroaryl group optionally having
substituents or cyclic amino group optionally having substituents,
[0015]W1 and W2[0016]are the same or different and each is a
bond or alkylene(Cn) optionally having substituents wherein n is an
integer of 1 to 3, [0017]X is oxygen atom or sulfur atom, [0018]Y is a
bond, oxygen atom, --CO--, --N(R7)-- wherein R7 is hydrogen
atom or alkyl group optionally having substituents, --SOm-- wherein
m is an integer of 0 to 2, --CON(R8)-- wherein R8 is hydrogen
atom or alkyl group optionally having substituents or --N(R9)CO--
wherein R9 is hydrogen atom or alkyl group optionally having
substituents), and [0019]Z is a bond or alkylene group optionally having
substituents (hereinafter sometimes abbreviated as amide derivative
(1)),an optically active form thereof or pharmaceutically acceptable salt
thereof.2. The amide derivative of the above-mentioned 1, wherein, in the
formula (1),R1, R2 and R3 are the same or different and
each is hydrogen atom, alkyl group optionally having substituents,
alkenyl group optionally having substituents, alkynyl group optionally
having substituents, cycloalkyl group, alkoxy group optionally having
substituents, acyloxy group optionally having substituents, halogen atom,
hydroxyl group, nitro group, cyano group, acyl group, mercapto group,
alkylthio group, alkylsulfonyl group, amino group, alkylamino group,
dialkylamino group, cyclic amino group, carbamoyl group, alkoxycarbonyl
group, carboxyl group, tetrazolyl group, oxadiazolyl group, sulfamoyl
group or haloalkyl group,a, b, c, d and e are each carbon atom, or 1 or 2
of a, b, c, d and e is(are) nitrogen atom(s) and the rest are carbon
atoms,R4, R5 and R6 are the same or different and each is
hydrogen atom, alkyl group optionally having substituents, alkenyl group
optionally having substituents, alkynyl group optionally having
substituents, cycloalkyl group, alkoxy group optionally having
substituents, acyloxy group optionally having substituents, halogen atom,
hydroxyl group, nitro group, cyano group, acyl group, mercapto group,
alkylthio group, alkylsulfonyl group, amino group, alkylamino group,
dialkylamino group, cyclic amino group, carbamoyl group, alkoxycarbonyl
group, carboxyl group, tetrazolyl group, oxadiazolyl group, sulfamoyl
group or haloalkyl group,A is hydrogen atom, cycloalkyl group, aryl group
optionally having substituents, heteroaryl group optionally having
substituents or cyclic amino group,W1 and W2 are the same or
different and each is a bond or alkylene (Cn) optionally having
substituents wherein n is an integer of 1 to 3,X is oxygen atom or sulfur
atom,Y is a bond, oxygen atom, --CO--, --N(R7)-- wherein R7 is
hydrogen atom or alkyl group optionally having substituents, --SOm--
wherein m is an integer of 0 to 2, --CON(R8)-- wherein R8 is
hydrogen atom or alkyl group optionally having substituents or
--N(R9)CO-- wherein R9 is hydrogen atom or alkyl group
optionally having substituents, andZ is a bond or alkylene group
optionally having substituents,an optically active form thereof or a
pharmaceutically acceptable salt thereof.3. The amide derivative of the
above-mentioned 2, wherein a, b, c, d and e in the formula (1) are all
carbon atoms,an optically active form thereof or a pharmaceutically
acceptable salt thereof.4. The amide derivative of the above-mentioned 1,
wherein R1, R2 and R3 in the formula (1) are the same or
different and each is hydrogen atom, alkyl group having 2 to 4 carbon
atoms or alkoxy group,an optically active form thereof or a
pharmaceutically acceptable salt thereof.5. The amide derivative of the
above-mentioned 1, wherein R1, R2 and R3 in the formula
(1) are the same or different and each is hydrogen atom, alkyl group
having 2 to 4 carbon atoms or alkoxy group having 2 to 4 carbon atoms,an
optically active form thereof or a pharmaceutically acceptable salt
thereof.6. The amide derivative of the above-mentioned 1, wherein
R1, R2 and R3 in the formula (1) are the same or different
and each is hydrogen atom, alkyl group having 2 to 4 carbon atoms or
methoxy group,an optically active form thereof or a pharmaceutically
acceptable salt thereof.7. The amide derivative of the above-mentioned 1,
wherein R4, R5 and R6 in the formula (1) are the same or
different and each is hydrogen atom, alkyl group optionally having
substituents, alkoxy group optionally having substituents, acyloxy group
optionally having substituents, halogen atom, hydroxyl group, amino
group, alkylamino group, dialkylamino group, cyclic amino group, carboxyl
group, haloalkyl group or haloalkyloxy group,an optically active form
thereof or a pharmaceutically acceptable salt thereof.8. The amide
derivative of the above-mentioned 1, wherein R4, R5 and R6
in the formula (1) are the same or different and each is hydrogen atom,
alkyl group optionally having substituents, alkoxy group optionally
having substituents, acyloxy group optionally having substituents,
halogen atom, hydroxyl group, amino group, alkylamino group, dialkylamino
group, cyclic amino group, carboxyl group or haloalkyl group,an optically
active form thereof or a pharmaceutically acceptable salt thereof.9. The
amide derivative of the above-mentioned 1, wherein Z of the formula (1)
is --CH2--,an optically active form thereof or a pharmaceutically
acceptable salt thereof.10. The amide derivative of the above-mentioned
1, wherein A of the formula (1) is aryl group optionally having
substituents or heteroaryl group optionally having substituents,an
optically active form thereof or a pharmaceutically acceptable salt
thereof.11. The amide derivative of the above-mentioned 1, wherein A of
the formula (1) is phenyl group optionally having substituents, pyridyl
group optionally having substituents, pyrazolyl group optionally having
substituents, thiazolyl group optionally having substituents, oxazolyl
group optionally having substituents or thienyl group optionally having
substituents,an optically active form thereof or a pharmaceutically
acceptable salt thereof.12. The amide derivative of the above-mentioned
1, wherein A of the formula (1) is phenyl group optionally having
substituents or a nitrogen-containing heterocyclic group selected from
the group consisting of the following formulas (Aa)-(Ac)

##STR00003##

[0019]wherein R10 is hydrogen atom, alkyl group optionally having
substituents, alkenyl group optionally having substituents, alkynyl group
optionally having substituents, cycloalkyl group, alkoxy group optionally
having substituents, acyloxy group optionally having substituents,
halogen atom, hydroxyl group, nitro group, cyano group, acyl group,
mercapto group, alkylthio group, alkylsulfonyl group, amino group,
alkylamino group, dialkylamino group, cyclic amino group, carbamoyl
group, alkoxycarbonyl group, carboxyl group, tetrazolyl group,
oxadiazolyl group, sulfamoyl group or haloalkyl group,an optically active
form thereof or a pharmaceutically acceptable salt thereof.13. The amide
derivative of the above-mentioned 1, wherein X of the formula (1) is
oxygen atom,an optically active form thereof or a pharmaceutically
acceptable salt thereof.14. The amide derivative of the above-mentioned
1, wherein --W1--Y--W2-- of the formula (1) is
--(CH2)2--, --(CH2)3-- or --(CH2)2O--,an
optically active form thereof or a pharmaceutically acceptable salt
thereof.15. The amide derivative of any of the above-mentioned 1, wherein
R1, R2 and R3 of the formula (1) are the same or different
and each is hydrogen atom, alkyl group having 2 to 4 carbon atoms or
alkoxy group having 2 to 4 carbon atoms,a, b, c, d and e are each carbon
atom, or either b or d is nitrogen atom and the rest are carbon
atoms,R4, R5 and R6 are the same or different and each is
hydrogen atom, methoxy group, halogen atom or hydroxyl group,

Z is --CH2--,

[0020]A is phenyl group optionally having substituents or
nitrogen-containing heterocyclic group selected from the group consisting
of the following formulas (Aa')-(Ae')

##STR00004##

wherein R10a, R11 and R12 are the same or different and
each is hydrogen atom, alkyl group optionally having substituents,
cycloalkyl group optionally having substituents, aryl group optionally
having substituents, heteroaryl group optionally having substituents,
arylalkyl group optionally having substituents, heteroarylalkyl group
optionally having substituents, alkoxy group optionally having
substituents, aryloxy group, arylalkyloxy group, halogen atom, hydroxyl
group, nitro group, cyano group, alkylthio group, amino group, alkylamino
group, dialkylamino group, cyclic amino group, haloalkyl group,
haloalkyloxy group,
R13O(CH2)jO(CH2)kO(CH2)lO-- wherein j,
k and l are each independently an integer of 2 to 10, R13 is
hydrogen atom, alkyl group optionally having substituents, cycloalkyl
group optionally having substituents, aryl group optionally having
substituents, heteroaryl group optionally having substituents, arylalkyl
group optionally having substituents, heteroarylalkyl group optionally
having substituents or haloalkyl group, or
R13O(CH2)jO(CH2)kO-- wherein j, k and R13
are as defined above, R10b is hydrogen atom, alkyl group optionally
having substituents, cycloalkyl group optionally having substituents,
aryl group optionally having substituents, heteroaryl group optionally
having substituents, arylalkyl group optionally having substituents,
heteroarylalkyl group optionally having substituents, haloalkyl group,
haloalkyloxy group,
R13O(CH2)jO(CH2)kO(CH2)l-- wherein j,
k, l and R13 are as defined above, or
R13O(CH2)jO(CH2)k-- wherein j, k and R13
are as defined above,X is oxygen atom, and

[0130]Some of the terms to be used in the present specification are
defined as follows.

[0131]The "substances that bind to a C5a receptor" means C5a, a
hydrolysates of C5a (e.g., C5a desArg wherein the carboxy terminal
arginine of C5a has been deleted), and known or unknown substances, which
are other than C5a, having affinity for C5a receptor.

[0132]The "C5a receptor antagonist" are substances that inhibit the bond
between a C5a receptor and "substances that bind to a C5a receptor".

[0133]The "C5a receptor antagonistic action" means an action that inhibits
a reaction that causes some physiological changes (e.g., increase of
intracellular Ca2+, and the like) by binding, via C5a receptor, of
"substances that bind to a C5a receptor" to cells that express the C5a
receptor.

[0134]In the present specification, each symbol is as defined in the
following.

[0137]In R1-R6 and R10, the alkynyl group is straight chain
or branched chain alkynyl having 2 to 18, preferably 2 to 12, more
preferably 2 to 5, carbon atoms, such as ethynyl, 2-propynyl, 2-butynyl,
5-pentynyl, 2-octynyl, 2-dodecynyl and the like.

[0138]In R1-R6, R10-R13, R10a, R10b and A,
the cycloalkyl group, for example, is cycloalkyl preferably having 3 to 7
carbon atoms, such as cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl
and the like.

[0140]In R1-R6 and R10, the acyloxy group is, for example,
alkanoyloxy having 2 to 9 carbon atoms, such as acetoxy, propionyloxy,
butyryloxy, isobutyryloxy, 2-methylbutyryloxy, 2,2-dimethylbutyryloxy,
3,3-dimethylbutyryloxy, valeryloxy, isovaleryloxy, hexanoyloxy,
heptanoyloxy, octanoyloxy, nonanoyloxy and the like,
cycloalkylcarbonyloxy having 4 to 8 carbon atoms, such as
cyclopentylcarbonyloxy, cyclohexylcarbonyloxy and the like,
arylcarbonyloxy having 7 to 11 carbon atoms, such as benzoyloxy,
naphthoyloxy and the like, and the like.

[0142]In R1-R6 and R10, the acyl group is, for example,
alkanoyl having 1 to 8, preferably 2 to 8, carbon atoms, such as formyl,
acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, hexanoyl,
octanoyl and the like, cycloalkylcarbonyl having 4 to 8 carbon atoms
(cycloalkyl moiety is same as the aforementioned cycloalkyl), such as
cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl and the
like, aroyl having 7 to 11 carbon atoms, such as benzoyl, toluoyl,
naphthoyl and the like, heteroarylcarbonyl such as nicotinoyl, thenoyl,
furoyl and the like, and the like.

[0144]In R1-R6 and R10, the alkylsulfonyl group is
alkylsulfonyl group wherein the alkyl moiety is as defined for the
above-mentioned "alkyl group" (straight chain or branched chain alkyl
having 1 to 18, preferably 1 to 12, carbon atoms). Examples thereof
include methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group
and the like.

[0145]In R1-R6, R10-R12 and R10a, the alkylamino
group is alkylamino group wherein the alkyl moiety is as defined for the
above-mentioned "alkyl group". Examples thereof include methylamino
group, ethylamino group, propylamino group, isopropylamino group and the
like.

[0146]In R1-R6, R10-R12 and R10a, the
dialkylamino group is that wherein each alkyl moiety is as defined for
the above-mentioned "alkyl group" and respective alkyl may be the same or
different. Examples thereof include dimethylamino group, diethylamino
group, dipropylamino group, diisopropylamino group, ethylmethylamino
group, butylmethylamino group and the like.

[0147]The cyclic amino group in R1-R6, R10-R12,
R10a and A is a 3 to 8-membered saturated cyclic amino group that
may contain one or more oxygen atoms and sulfur atoms as
ring-constituting atoms, besides carbon atom and nitrogen atom. Examples
thereof include aziridinyl, azetidinyl, pyrrolizinyl, piperidino,
piperidyl, piperazino, piperazinyl, azepinyl, morpholino, morpholinyl,
thiomorpholinyl, imidazolidinyl, heptamethyleneimino and the like.

[0148]In R1-R6, the sulfamoyl group is sulfamoyl group
optionally mono- or di-substituted with lower alkyl having 1 to 3 carbon
atoms. Examples thereof include sulfamoyl, methylsulfamoyl,
ethylsulfamoyl, dimethylsulfamoyl and the like.

[0149]In R1-R6, R10-R13, R10a and R10b, the
haloalkyl group is alkyl substituted by one or more halogen atoms which
is as the aforementioned "halogen atom", wherein the alkyl moiety is as
defined for the aforementioned "alkyl group". Examples thereof include
fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl,
chloromethyl, trichloromethyl and the like.

[0150]In the haloalkyloxy group for R4-R6, R11, R12,
R10a and R10b, "haloalkyl" is as defined for the aforementioned
haloalkyl. Examples of haloalkyloxy group include trifluoromethyloxy,
2,2,2-trifluoroethyloxy and the like.

[0151]In R1-R6, R11-R13, R10a, R10b and A,
the aryl group is, for example, aryl having 6 to 14 carbon atoms such as
phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl and the like. The
aryl may have one or more substituents wherein the position of
substitution is not particularly limited. The substituents may form a
ring, may be condensed with aryl and may be partially reduced.

[0152]In R1-R6, R11-R13, R10a, R10b and A,
the heteroaryl is a 5- to 14-membered ring group that contains one or
more hetero atoms such as nitrogen atom, oxygen atom, sulfur atom and the
like as ring-constituting atoms, besides carbon atom, may be monocyclic
or polycyclic and may be partially reduced. Examples thereof include
pyridyl, thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl,
isoxazolyl, thiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl,
indolinyl, benzofuranyl, 2,3-dihydrobenzofuranyl, benzothienyl,
benzoxazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl,
quinoxalinyl, quinazolinyl, phenazinyl, tetrazolyl, oxadiazolyl,
imidazothienyl, 1,3-dioxaindanyl, 4-oxachromanyl and the like. These
heteroaryl groups optionally have one or more substituents, where the
position of substitution is not particularly limited. In the case of a
polycycle, any ring may be substituted. The bond may be present on any
ring, if it is possible.

[0153]When any two of R1, R2 and R3 in combination with the
adjacent carbon atom form a ring, it may be condensed with aryl (the
"aryl" here is as defined above), or partially reduced. In addition, the
ring may contain one or more hetero atoms such as nitrogen atom, oxygen
atom, sulfur atom and the like to form heteroaryl (the "heteroaryl" here
is as defined above), and a ring wherein the heteroaryl is partially
reduced is also encompassed.

[0154]In R1-R6 and R10, the alkoxycarbonyl group is that
wherein the alkoxy moiety is as defined for the above-mentioned "alkoxy
group". The alkoxycarbonyl group is exemplified by methoxycarbonyl group,
ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group,
tertiary butoxycarbonyl group and the like.

[0155]In R1-R6, the acylamino group is that wherein the acyl
group is as defined for the above-mentioned "acyl". In addition,
alkylsulfonylamino and arylsulfonylamino are also encompassed in
acylamino, wherein the "alkyl" and "aryl" here are as defined above.
Examples of the acylamino group include acetamide, benzamide and the
like.

[0157]In R1-R6, R11, R12, R10a, R10b and
R13, the arylalkyl is that wherein the aryl moiety is as defined for
the aforementioned "aryl group" and the alkyl moiety is straight chain or
branched chain alkyl having 1 to 12, preferably 1 to 3, carbon atoms.
Examples of arylalkyl include benzyl, 2-phenylethyl, 3-phenylpropyl,
1-naphthylmethyl, 2-(1-naphthyl)ethyl, 2-naphthylmethyl,
2-(2-naphthyl)ethyl and the like. The aryl moiety of arylalkyl may have
one or more substituents, where the position of substitution is not
particularly limited.

[0158]In R1-R6, R11, R12, R10a, R10b and
R13, the heteroarylalkyl group is that wherein the heteroaryl moiety
is as defined for the aforementioned "heteroaryl group" and the alkyl
moiety is straight chain or branched chain alkyl having 1 to 12,
preferably 1 to 3, carbon atoms. Examples of heteroarylalkyl include
2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-thienylmethyl,
3-thienylmethyl, 2-furylmethyl, 3-furylmethyl, 2-pyrrolylmethyl,
3-pyrrolylmethyl, 3-pyrazolylmethyl, 4-pyrazolylmethyl,
5-pyrazolylmethyl, 2-imidazolylmethyl, 4-imidazolylmethyl,
5-imidazolylmethyl, 2-oxazolylmethyl, 4-oxazolylmethyl, 5-oxazolylmethyl,
3-isoxazolylmethyl, 4-isoxazolylmethyl, 5-isoxazolylmethyl,
2-thiazolylmethyl, 4-thiazolylmethyl, 5-thiazolylmethyl,
3-isothiazolylmethyl, 4-isothiazolylmethyl, 5-isothiazolylmethyl,
2-(2-pyridyl)ethyl, 2-(3-pyridyl)ethyl, 2-(4-pyridyl)ethyl,
2-(2-thienyl)ethyl, 2-(3-thienyl)ethyl, 2-(2-thiazolyl)ethyl,
2-(4-thiazolyl)ethyl, 2-(5-thiazolyl)ethyl and the like. The heteroaryl
moiety of heteroarylalkyl group may have one or more substituents, where
the position of substitution is not particularly limited.

[0159]In R1-R6, the carbamoyl group optionally having
substituents is a carbamoyl group optionally mono or di-substituted by
lower alkyl having 1 to 3 carbon atoms. Examples thereof include
carbamoyl, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl and the
like.

[0160]In R1-R6, R11, R12 and R10a, the aryloxy
group is that wherein the aryl moiety is as defined for the
aforementioned "aryl group". Examples of aryloxy group include phenoxy
and the like.

[0161]In R1-R6, R11, R12 and R10a, the
arylalkyloxy group is that wherein the arylalkyl moiety is as defined for
the aforementioned "arylalkyl". Examples of arylalkyloxy group include
benzyloxy and the like.

a, b, c, d and e are each carbon atom, or one or two of a, b, c, d and e
is(are) nitrogen atom(s) and the rest are carbon atoms,R4, R5
and R6 are the same or different and each is hydrogen atom, alkyl
group optionally having substituents, alkenyl group optionally having
substituents, alkynyl group optionally having substituents, cycloalkyl
group, alkoxy group optionally having substituents, acyloxy group
optionally having substituents, halogen atom, hydroxyl group, nitro
group, cyano group, acyl group, mercapto group, alkylthio group,
alkylsulfonyl group, amino group, alkylamino group, dialkylamino group,
cyclic amino group, carbamoyl group, alkoxycarbonyl group, carboxyl
group, tetrazolyl group, oxadiazolyl group, sulfamoyl group or haloalkyl
group,A is hydrogen atom, cycloalkyl group, aryl group optionally having
substituents, heteroaryl group optionally having substituents or cyclic
amino group,W1 and W2 are the same or different and each is a
bond or alkylene (Cn) optionally having substituents wherein n is an
integer of 1 to 3,X is oxygen atom or sulfur atom,Y is a bond, oxygen
atom, --CO-- and --N(R7)-- wherein R7 is hydrogen atom or alkyl
group optionally having substituents, --SOm-- wherein m is an
integer of 0 to 2, --CON(R8)-- wherein R8 is hydrogen atom or
alkyl group optionally having substituents, or --N(R9)CO-- wherein
R9 is hydrogen atom or alkyl group optionally having substituents,
andZ is a bond or alkylene group optionally having substituents, an
optically active form thereof or a pharmaceutically acceptable salt
thereof is preferable. At this time, a, b, c, d and e are preferably all
carbon atoms.

[0164]The R1, R2 and R3 of the formula (1) are preferably
the same or different and each is hydrogen atom, alkyl group having 2 to
4 carbon atoms or alkoxy group, more preferably hydrogen atom, alkyl
group having 2 to 4 carbon atoms or alkoxy group having 2 to 4 carbon
atoms, still more preferably hydrogen atom, alkyl group having 2 to 4
carbon atoms or methoxy group.

[0165]As R1, preferred is alkyl group having 2 to 4 carbon atoms or
alkoxy group having 2 to 4 carbon atoms. As R2 and R3,
preferred is hydrogen atom.

[0166]As R4, R5 and R6 of the formula (1), preferred are
the same or different and each is hydrogen atom, alkyl group optionally
having substituents, alkoxy group optionally having substituents, acyloxy
group optionally having substituents, halogen atom, hydroxyl group, amino
group, alkylamino group, dialkylamino group, cyclic amino group, carboxyl
group, haloalkyl group or haloalkyloxy group, more preferred is hydrogen
atom, alkyl group optionally having substituents, alkoxy group optionally
having substituents, acyloxy group optionally having substituents,
halogen atom, hydroxyl group, amino group, alkylamino group, dialkylamino
group, cyclic amino group, carboxyl group or haloalkyl group.

[0167]As A of the formula (1), preferred is aryl group optionally having
substituents or heteroaryl group optionally having substituents, more
preferred is phenyl group optionally having substituents, pyridyl group
optionally having substituents, pyrazolyl group optionally having
substituents, thiazolyl group optionally having substituents, oxazolyl
group optionally having substituents or thienyl group optionally having
substituents, still more preferred is phenyl group optionally having
substituents or nitrogen-containing heterocyclic group selected from the
group consisting of the following formulas (Aa)-(Ac)

wherein R10a, R11 and R12 are the same or different and
each is hydrogen atom, alkyl group optionally having substituents,
cycloalkyl group optionally having substituents, aryl group optionally
having substituents, heteroaryl group optionally having substituents,
arylalkyl group optionally having substituents, heteroarylalkyl group
optionally having substituents, alkoxy group optionally having
substituents, aryloxy group, arylalkyloxy group, halogen atom, hydroxyl
group, nitro group, cyano group, alkylthio group, amino group, alkylamino
group, dialkylamino group, cyclic amino group, haloalkyl group,
haloalkyloxy group,
R13O(CH2)jO(CH2)kO(CH2)lO-- wherein j,
k, l and R13 are as defined above or
R13O(CH2)jO(CH2)kO-- wherein j, k and R13
are as defined above, R10b is hydrogen atom, alkyl group optionally
having substituents, cycloalkyl group optionally having substituents,
aryl group optionally having substituents, heteroaryl group optionally
having substituents, arylalkyl group optionally having substituents,
heteroarylalkyl group optionally having substituents, haloalkyl group,
R13O(CH2)jO(CH2)kO(CH2)l-- wherein j,
k, l and R13 are as defined above, or
R13O(CH2)jO(CH2)k-- wherein j, k and R13
are as defined above.

[0168]As --W1--Y--W2-- of the formula (1), --(CH2)2--,
--(CH2)3-- or --(CH2)2O-- is preferable.

[0169]It is preferable that a, b, c, d and e of the formula (1) be
preferably all carbon atoms, or that b (or d) be nitrogen atom and the
rest be carbon atoms.

[0170]The case where the R1, R2 and R3 of the formula (1)
are the same or different and each is hydrogen atom, alkyl group having 2
to 4 carbon atoms or alkoxy group having 2 to 4 carbon atoms,

a, b, c, d and e are each carbon atom, or either b or d is nitrogen atom
and the rest are carbon atoms,R4, R5 and R6 are the same
or different and each is hydrogen atom, methoxy group, halogen atom or
hydroxyl group,

Z is --CH2--,

[0171]A is phenyl group optionally having substituents or a
nitrogen-containing heterocyclic group selected from the group consisting
of the following formulas (Aa')-(Ae')

##STR00007##

wherein R10a, R11 and R12 are the same or different and
each is hydrogen atom, alkyl group optionally having substituents,
cycloalkyl group optionally having substituents, aryl group optionally
having substituents, heteroaryl group optionally having substituents,
arylalkyl group optionally having substituents, heteroarylalkyl group
optionally having substituents, alkoxy group optionally having
substituents, aryloxy group, arylalkyloxy group, halogen atom, hydroxyl
group, nitro group, cyano group, alkylthio group, amino group, alkylamino
group, dialkylamino group, cyclic amino group, haloalkyl group,
haloalkyloxy group,
R13O(CH2)jO(CH2)kO(CH2)lO-- wherein j,
k, 1 and R13 are as defined above or
R13O(CH2)jO(CH2)kO-- wherein j, k and R13
are as defined above, R10b is hydrogen atom, alkyl group optionally
having substituents, cycloalkyl-group optionally having substituents,
aryl group optionally having substituents, heteroaryl group optionally
having substituents, arylalkyl group optionally having substituents,
heteroarylalkyl group optionally having substituents, haloalkyl group,
haloalkyloxy group,
R13O(CH2)jO(CH2)kO(CH2)l-- wherein j,
k, l and R13 are as defined above or
R13O(CH2)jO(CH2)k-- wherein j, k and R13
are as defined above,X is oxygen atom, and--W1--Y--W2-- is
--(CH2)2-- or --(CH2)3-- is particularly preferable.

[0172]As X of the formula (1), oxygen atom is preferable.

[0173]As --W1--Y--W2-- of the formula (1), --(CH2)2--
or --(CH2)3-- is preferable.

[0284]The pharmaceutically acceptable salt of the compound of the formula
(1) is preferably exemplified by a salt with inorganic acid such as
hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,
nitric acid and the like, a salt with organic acid such as acetic acid,
propionic acid, succinic acid, glycolic acid, lactic acid, malic acid,
tartaric acid, citric acid, maleic acid, fumaric acid, methanesulfonic
acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid,
ascorbic acid and the like, a salt with alkali metal (lithium, sodium,
potassium and the like), a salt with alkaline earth metal (calcium,
magnesium and the like), a salt with metal such as aluminum and the like,
salt with organic base such as piperidine, piperazine, morpholine,
diethanolamine, ethylenediamine and the like.

[0285]The present invention encompasses solvates (e.g., hydrate) of the
compound of the above-mentioned formula (1) or a salt thereof, prodrug
metabolized in vivo to be converted to the compound of the formula (1),
and active metabolites of the compound of the formula (1).

[0286]The compound of the present invention further encompasses any form
of an optically pure enantiomer, a diastereomer and a mixture of these.

[0287]While the compound of the present invention can be produced by the
following methods, the production method is not limited to them. The
methods exemplified here may be used alone or in combination and a
conventional method may be further combined. Where necessary, each
compound is protected or deprotected by a conventional method.

[0288]The compound (1a) wherein X of the formula (1) is oxygen atom can be
produced by the following methods 1-3.

[0290]For step 1, a known amidation method or peptide synthesis method and
the like can be used for example, the reaction is carried out in the
presence of a condensing agent (e.g., carbodiimide
(N,N-dicyclohexylcarbodiimide,
1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide and the like),
diphenylphosphorylazide, carbonyldiimidazole, 1-benzotriazolyloxy
tris(dimethylamino)phosphonium hexafluorophosphate (Bop reagent),
2-chloro-N-methylpyridinium iodide-tributylamine system (Mukaiyama
Method), N-cyclohexylcarbodiimide-N'-methylpolystyrene and the like, in
an inert solvent or without solvent at preferably from -20° C. to
80° C. In step 1, a deoxydation agent [e.g., organic base (e.g.,
triethylamine, N-methylmorpholine, pyridine, dimethylaniline and the
like), inorganic base (e.g., sodium hydrogencarbonate, potassium
carbonate, sodium hydroxide and the like)] and the like may be present.
Generally, the reaction of step 1 is completed within 24 hr.

[0291]The compound (1a) in step 1 can be also produced by converting
compound (3) to a different reactive derivative. When the reactive
derivative of compound (3) is acid halide (e.g., acid chloride, acid
bromide and the like) or acid anhydride (e.g., symmetric acid anhydride,
mixed acid anhydride of lower alkyl carbonate, mixed acid anhydride of
alkyl phosphate and the like), the reaction with compound (2) is
generally carried out in an inert solvent or without solvent at from
-20° C. to 80° C.

[0292]Furthermore, when what is called an active ester (4-nitrophenyl
ester, 4-chlorobenzyl ester, 4-chlorophenyl ester, pentafluorophenyl
ester, succinimide ester, benzotriazole ester, 4-dimethylsulfonium phenyl
ester and the like) is used as the reactive derivative of compound (3),
the reaction is generally carried out in an inert solvent or without
solvent at a temperature of from -20° C. to the refluxing
temperature of the solvent.

[0293]The inert solvent to be used in the aforementioned amidation is
exemplified by hydrocarbons such as hexane, benzene, toluene, xylene and
the like, halogenated hydrocarbons such as chloroform, dichloromethane,
dichloroethane and the like, ethers such as tetrahydrofuran (hereinafter
to be abbreviated as THF), dioxane and the like, esters such as ethyl
acetate and the like, ketones such as acetone, methyl ethyl ketone and
the like, alcohols such as methanol, ethanol, isopropyl alcohol and the
like, amides such as N,N-dimethylformamide (hereinafter to be abbreviated
as DMF), dimethylacetamide (hereinafter to be abbreviated as DMA) and the
like, acetonitrile, dimethyl sulfoxide, water and a mixed solvent thereof
and the like.

Method 2: Production Method 2 of Compound (1a)

##STR00009##

[0294]wherein R1, R2, R3, R4, R5, R6, a, b,
c, d, e, A, W1, W2, Y and Z are as defined above, and L is a
leaving group such as halogen atom, methanesulfonyoxy or
para-toluenesulfonyloxy and the like.

[0295]The compound (1a) can be produced by reacting compound (4) with
compound (5).

[0296]In step 2, the reaction is carried out in a solvent that does not
inhibit the reaction, in the presence of a deoxydation agent [e.g.,
organic base (e.g., triethylamine, N-methylmorpholine, pyridine,
dimethylaniline and the like), inorganic base (e.g., sodium hydride,
sodium hydrogencarbonate, potassium carbonate, sodium hydroxide and the
like)] and the like at from -20° C. to the refluxing temperature
of the solvent. The solvent to be used in step 2 is exemplified by
hydrocarbons such as hexane, benzene, toluene and the like, halogenated
hydrocarbons such as chloroform, dichloromethane, dichloroethane and the
like, ethers such as THF, dioxane and the like, esters such as acetic
acid ester and the like, ketones such as acetone, methyl ethyl ketone and
the like, alcohols such as methanol, ethanol, isopropyl alcohol and the
like, amides such as DMF, DMA and the like, acetonitrile, DMSO, water or
a mixed solvent thereof and the like.

[0299]Step 3 is carried out in a solvent that does not inhibit the
reaction in the presence of a deoxydation agent such as an organic base
(e.g., triethylamine, N-methylmorpholine, pyridine, dimethylaniline and
the like) or an inorganic base (e.g., sodium hydride, sodium
hydrogencarbonate, potassium carbonate, sodium hydroxide and the like)
and, where necessary, a catalyst such as copper, copper iodide and the
like at a temperature from -20° C. to the refluxing temperature of
the solvent. The solvent to be used in step 3 is exemplified by
hydrocarbons such as hexane, benzene, toluene and the like, halogenated
hydrocarbons such as chloroform, dichloromethane, dichloroethane and the
like, ethers such as THF, dioxane and the like, esters such as acetic
acid ester and the like, ketones such as acetone, methyl ethyl ketone and
the like, alcohols such as methanol, ethanol, isopropyl alcohol and the
like, amides such as DMF, DMA and the like, nitrobenzene, acetonitrile,
DMSO, water or a mixed solvent thereof and the like.

Method 4: Production Method of Compound (1b) Wherein X of the Formula (1)
is Sulfur Atom

[0301]The compound (1b) can be produced from compound (1a) by the
above-mentioned routes (step 4).

[0302]Step 4 is carried out in a solvent that does not inhibit the
reaction in the presence of
2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetan-2,4-disulfide
(Lawesson's reagent), diphosphorus pentasulfide and the like.

[0303]The solvent to be used in step 4 is exemplified by benzene, toluene,
xylene, THF, pyridine and the like. The reaction is carried out at a
temperature of generally from 0° C. to the refluxing temperature
of the solvent. While the reaction time varies depending on the reaction
temperature, it is generally 1 hr-24 hr.

Method 5: Production Method of Compound (9) Wherein R4 of the Formula
(1) is Hydroxyl Group and R5 and R6 are Hydrogen Atoms

[0305]The compound (9) can be produced by eliminating the protecting group
M of compound (8) (step 5).

[0306]The protecting group M is exemplified by methyl, benzyl, substituted
benzyl, benzyloxycarbonyl and the like.

[0307]The protecting group can be eliminated by a conventional method such
as hydrolysis, acid treatment, hydrogenolysis with metal catalyst
(palladium carbon, Raney-nickel and the like), depending on the kind of
the protecting group, and the like.

Synthetic Method of Starting Material Compound

[0308]The compound (2) to be the starting material of method 1 can be
produced by the following methods 6-8.

Method 6: Production Method of Compound (2)

##STR00013##

[0309]wherein T is amino-protecting group such as acetyl, t-butoxycarbonyl
and the like and R1, R2, R3, a, b, c, d, e, A, Z and L are
as defined above.

[0310]The compound (10) and compound (5) are reacted in a suitable solvent
in the presence of a base to give compound (11), and then a protecting
group is eliminated to give compound (2) (steps 6 and 7).

[0311]The solvent to be used in step 6 is exemplified by methanol,
ethanol, propanol, isopropyl alcohol, methylene chloride, chloroform,
THF, dioxane, benzene, toluene, xylene, DMF, DMSO and the like. The base
to be used is exemplified by sodium hydride, sodium carbonate, potassium
carbonate, sodium hydrogencarbonate, sodium hydroxide, potassium
hydroxide, triethylamine, diisopropylethylamine, pyridine and the like.
While the reaction temperature varies depending on the solvent, it is
generally 0° C.-140° C., and while the reaction time varies
depending on the reaction temperature, it is generally from 1 hr to 24
hr.

[0312]This reaction can be also carried out without the protecting group T
(when T is hydrogen atom), whereby compound (2) can be produced.

[0313]In step 7, the protecting group can be eliminated by a conventional
method such as hydrolysis, acid treatment and the like according to a
conventional method, depending on the kind of the protecting group.

Method 7: Production Method of Compound (15), Wherein, in Compound (2),
--Z--A is --CH(R11)--U--A (U is Alkylene Optionally Having
Substituents, R11 is Hydrogen Atom, Alkyl Optionally Having
Substituents, Aryl or Heteroaryl, and A is as Defined Above

##STR00014##

wherein R1, R2, R3, a, b, c, d, e, A, R11 and U are as
defined above.

[0314]The compound (12) and compound (13) are subjected to dehydration
condensation without solvent or in a suitable solvent to give compound
(14), which compound is then reduced in a suitable solvent, whereby
compound (15) can be produced (steps 8 and 9).

[0315]The dehydration condensation reaction of compound (12) and compound
(13) in step 8 can be carried out in the presence of a dehydrating agent
or by removing the generated water from the reaction system with
Dean-Stark trap.

[0316]As the dehydrating agent to be used for this reaction, a
conventional dehydrating agent can be used. Examples of the dehydrating
agent include anhydrous magnesium sulfate, molecular sieves and the like.
The solvent to be used for the reaction may be, for example, methylene
chloride, chloroform, benzene, toluene, xylene and the like. While the
reaction temperature varies depending on the solvent, it is generally
from 0° C. to 150° C., and while the reaction time varies
depending on the reaction temperature, it is generally 1 hr-24 hr.

[0317]The reducing agent to be used for step 9 is exemplified by sodium
borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride,
formic acid, sodium formate and the like. When sodium
triacetoxyborohydride or sodium cyanoborohydride is used as a reducing
agent, removal of water using the dehydrating agent or Dean-Stark trap in
step 8 can be omitted. The solvent to be used for the reaction includes,
for example, water, methanol, ethanol, propanol, THF, dioxane,
1,2-dichloroethane, acetic acid and the like, and a mixed solvent thereof
may be used. While the reaction temperature varies depending on the
solvent, it is generally from 0° C. to 80° C., and while
the reaction time varies depending on the reaction temperature, it is
generally from 1 hr to 24 hr.

Method 8: Production Method of Compound (18), Wherein, in Compound (2),
--Z--A is --CH2--U--A Wherein A and U are as Defined Above

[0319]The compound (12) or a salt thereof and compound (16) or a reactive
derivative thereof are reacted without solvent or in a suitable solvent
to give compound (17), which compound is then reacted with a reducing
agent in a suitable solvent, whereby compound (18) can be produced (steps
10 and 11).

[0320]The reaction of compound (12) or a salt thereof with compound (16)
in step 10 can be carried out in the same manner as in step 1.

[0321]The reducing agent to be used for reduction in step 11 is
exemplified by lithium aluminum hydride, borane and the like. The solvent
to be used for reduction is, for example, THF, diethyl ether, hexane and
the like; or a mixed solvent thereof. While the reaction temperature
varies depending on the solvent, it is generally from 0° C. to
65° C., and while the reaction time varies depending on the
reaction temperature, it is generally from 1 hr to 24 hr.

[0322]The compound (3) to be the starting material can be produced by the
following methods 9-10.

Method 9: Production Method 1 of Compound (3)

##STR00016##

[0324]The compound (3) to be used in Method 1 can be produced from
compound (19) wherein R1, R5, R6, W1, W2 and Y
are as defined above according to the method described in a reference
(Synthetic Communications, 12(10), 763-770, 1982) (step 12).

Method 10: Production Method 2of Compound (3)

##STR00017##

[0325]wherein R4, R5, R6, W1, W2, Y and L are as
defined above.

[0326]The compound (3) can be produced from compound (19) via steps 13-16.

[0327]The reducing agent to be used for the reduction in step 13 is, for
example, lithium aluminum hydride, sodium borohydride, lithium
borohydride, diborane and the like. The solvent to be used in step 13 is,
for example, water, methanol, ethanol, propanol, ether, THF, dioxane,
acetic acid and the like, or a mixed solvent thereof. While the reaction
temperature varies depending on the solvent, it is generally from
0° C. to 80° C., and while the reaction time varies
depending on the reaction temperature, it is generally from 1 hr to 24
hr.

[0328]When L of compound (21) in step 14 is chlorine atom, the reaction is
generally carried out in an inert solvent or without solvent in the
presence of thionyl chloride, methanesulfonyl chloride,
para-toluenesulfonyl chloride or triphenylphosphine, as necessary, in the
co-presence of an organic base such as triethylamine and the like, at
from -20° C. to 80° C. The solvent to be used then is, for
example, methylene chloride, chloroform, carbon tetrachloride, ether, DMF
and the like; or a mixed solvent thereof and the like.

[0329]When L of compound (21) is methanesulfonyoxy or
para-toluenesulfonyloxy, the reaction is generally carried out in an
inert solvent or without solvent in the presence of methanesulfonyl
chloride or para-toluenesulfonyl chloride in the co-presence of an
organic base such as triethylamine and the like at from -20° C. to
80° C. The solvent is to be used here is, for example, methylene
chloride, chloroform, ether, DMF or a mixed solvent thereof and the like.

[0330]The step 15 is carried out in a solvent that does not inhibit the
reaction in the presence of sodium cyanide, potassium cyanide,
tetraethylammonium cyanide and the like at a temperature of from
-20° C. to the refluxing temperature of the solvent. The solvent
to be used in step 15 includes water, ethanol, ethanol, propanol, ether,
DMF, DMSO, acetone, acetonitrile and a mixed solvent and the like.

[0331]The step 16 is carried out in a solvent that does not inhibit the
reaction in the presence of an inorganic base (e.g., sodium hydroxide,
potassium hydroxide, barium hydroxide and the like) or an acid (e.g.,
hydrochloric acid, hydrobromic acid, sulfuric acid and the like) at a
temperature of from -20° C. to the refluxing temperature of the
solvent. The solvent to be used in step 16 is, for example, water,
methanol, ethanol, propanol, ethylene glycol, ethylene glycol monomethyl
ether, DME, acetic acid, formic acid; or a mixed solvent thereof and the
like.

Method 11: Production Method of Compound (4), which is a Starting Material
of Method 2

[0340]When the crystal of obtained the compound of the present invention
is not a solvate and the like, the compound of the present invention can
be converted to a solvate by treating the compound with water,
water-containing solvent or other solvent.

[0341]The compound of the formula (1) of the present invention, a
pharmaceutically acceptable salt thereof and a solvate thereof show a C5a
receptor antagonistic action and are useful as a prophylactic or
therapeutic drug of diseases, in which C5a is involved, for example,
diseases or syndromes due to inflammation caused by C5a [e.g., autoimmune
diseases such as rheumatism and systemic lupus erythematosus and the
like; sepsis; adult respiratory distress syndrome; chronic obstructive
pulmonary disease; allergic diseases such as asthma and the like;
atherosclerosis; cardiac infarction; brain infarction; psoriasis;
Alzheimer's disease; serious organ injury (e.g., pneumonia, nephritis,
hepatitis and pancreatitis and the like) due to activation of leukocytes
caused by ischemia reperfusion, trauma, burn, surgical invasion, and the
like. In addition, they are useful as a prophylactic or therapeutic drug
of infectious diseases due to bacteria or virus that invades via a C5a
receptor.

[0342]When the compound of the present invention of the formula (1),
pharmaceutical acceptable salt thereof and solvate thereof are used for
the aforementioned prophylaxis or treatment, it is generally administered
systemically or topically and orally or parenterally. The dose to
patients varies depending on the age, body weight, sex, general health
conditions, treatment effect, diet, administration time, administration
method, clearance rate, combination of drugs, the condition of the
disease under treatment and the like. It is generally desirably in the
range of from 0.1 mg to 500 mg per dose for an adult by oral
administration once to several times a day, or in the range of from 0.01
mg to 200 mg per dose for an adult by parenteral administration
(preferably intravenous administration) once to several times a day.

[0343]Because the dose may change depending on various conditions as
mentioned above, when a dose smaller than the above-mentioned range may
be sufficient, a dose outside the above-mentioned range may be necessary.

[0344]The compound of the formula (1) of the present invention, a
pharmaceutically acceptable salt thereof and a solvate thereof can be
used orally or parenterally, for example, by inhalation, rectal
administration, topical administration and the like as a pharmaceutical
composition or preparation (e.g., powder, granule, tablet, pill, capsule,
syrup, elixir, suspension, solution and the like), wherein at least one
compound of the present invention can be used alone or used upon admixing
with a pharmaceutically acceptable carrier (excipient, binder,
disintegrant, corrigent, corrective, emulsifier, diluent and/or
dissolution aids and the like).

[0345]A pharmaceutical composition can be prepared according to a general
method. In the present specification, by the parenteral is meant
subcutaneous injection, intravenous injection, intramuscular injection,
intraperitoneal injection, drip and the like. A composition for
injection, such as sterile suspension for injection and oil suspension
can be prepared using a suitable dispersing agent, wetting agent, or
suspending agent according to a method known in the art.

[0348]Where necessary, the tablet and pill may be coated with a film of
gastric or enteric coating such as sucrose, gelatin,
hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate and the
like, or may be coated with two or more layers. In addition, they may
include a capsule of absorbable material such as gelatin.

[0349]The liquid composition for oral administration includes
pharmaceutically acceptable solution, suspension, syrup, elixir and the
like, and may contain a generally used inactive diluent (purified water,
ethanol). This composition may contain, besides the inactive diluent,
auxiliaries such as wetting agent, suspending agent, sweetening agent,
flavor, perfume and preservative. Other compositions for oral
administration are, for example, spray agent containing one or more
active substances and formulated by a method known per se.

[0350]The composition for injection for parenteral administration may
include sterile aqueous or non-aqueous solution, suspension and emulsion.
Examples of the aqueous solution and suspension include distilled water
for injection and physiological saline. Examples of the water insoluble
solution and suspension include propylene glycol, polyethylene glycol,
olive oil, ethanol, polysorbate 80 and the like. The above-mentioned
composition may further contain auxiliaries such as preservative, wetting
agent, emulsifier, dispersing agent, stabilizer (e.g., lactose and the
like) and dissolution aids (e.g., amino acid such as arginine, glutamic
acid, aspartic acid, and the like). These can be sterilized by, for
example, filtration through a bacteria-retaining filter, addition of
microbicide or irradiation.

[0351]The composition for injection can be used by producing a sterile
solid composition and dissolved, for example, the lyophilized product in
sterile water or sterile solvent for injection before use.

[0352]Other composition for parenteral administration include external
solution, ointment, liniment, suppository and the like, containing one or
more active substances and formulated by a conventional method.

[0353]The suppository for rectal administration can be produced by
admixing the drug and a suitable non-irritant vehicle, which is a
substance which is solid at ambient temperature but liquid at the
temperature of intestine and which melts in the rectum to release the
drug, such as cocoa butter and polyethylene glycols.

[0354]The amide derivative (1), an optically active form thereof or a
pharmaceutically acceptable salt thereof of the present invention are
useful as an active ingredient of a C5a receptor antagonist, which C5a
receptor antagonist can be used as a drug for the prophylaxis or
treatment of infectious diseases caused by bacteria or viruses that
invade via a C5a receptor, and can be used in combination with a
prophylactic or therapeutic drugs of autoimmunity disease, sepsis, adult
respiratory distress syndrome, chronic obstructive pulmonary disease,
allergic disease, atherosclerosis, cardiac infarction, cerebral
infarction, psoriasis, Alzheimer's disease, or serious organ injury due
to activation of leucytes caused by ischemia reperfusion, external
injuries, burn or surgical invasion.

[0355]The compound of the formula (1) of the present invention, optically
active form thereof or a pharmaceutically acceptable salt thereof is
expected to show a superior treatment effect by a combined use with an
agent for the prophylaxis or treatment of autoimmune diseases such as
rheumatism, systemic lupus erythematosus and the like; sepsis; adult
respiratory distress syndrome; chronic obstructive pulmonary disease;
allergic diseases such as asthma and the like; atherosclerosis; cardiac
infarction; brain infarction; psoriasis; Alzheimer's disease; or serious
organ injury (e.g., pneumonia, nephritis, hepatitis, pancreatitis and the
like) due to activation of leukocytes caused by ischemia reperfusion,
trauma, burn, surgical invasion and the like. As used herein, by the
"combined use" is meant a combination composition of the compound of the
present invention or a pharmaceutically acceptable salt thereof with an
agent for the prophylaxis or treatment of autoimmune diseases such as
rheumatism, systemic lupus erythematosus and the like; sepsis; adult
respiratory distress syndrome; chronic obstructive pulmonary disease;
allergic diseases such as asthma and the like; atherosclerosis; cardiac
infarction; brain infarction; psoriasis; Alzheimer's disease; or serious
organ injury (e.g., pneumonia, nephritis, hepatitis, pancreatitis and the
like) due to activation of leukocytes caused by ischemia reperfusion,
trauma, burn surgical invasion and the like, and the use as a potentiator
of an action of an agent for the prophylaxis or treatment of autoimmune
diseases such as rheumatism, systemic lupus erythematosus and the like;
sepsis; adult respiratory distress syndrome; chronic obstructive
pulmonary disease; allergic diseases such as asthma and the like;
atherosclerosis; cardiac infarction; brain infarction; psoriasis;
Alzheimer's disease; or serious organ injury (e.g., pneumonia, nephritis,
hepatitis, pancreatitis and the like) due to activation of leukocytes
caused by ischemia reperfusion, trauma, burn, surgical invasion and the
like, including combined use and concurrent use, wherein two or more
active ingredient compounds are simultaneously used or used in a
staggered manner with or without mixing. The pharmaceutical drug of the
present invention which is characterized by the combined use of the
compound represented by the above-mentioned formula (1), optically active
form thereof or a pharmaceutically acceptable salt thereof and an agent
for the prophylaxis or treatment of autoimmune diseases such as
rheumatism, systemic lupus erythematosus and the like; sepsis; adult
respiratory distress syndrome; chronic obstructive pulmonary disease;
allergic diseases such as asthma and the like; atherosclerosis; cardiac
infarction; brain infarction; psoriasis; Alzheimer's disease; or serious
organ injury (e.g., pneumonia, nephritis, hepatitis, pancreatitis and the
like) due to activation of leukocytes caused by ischemia reperfusion,
trauma, burn, surgical invasion and the like is not particularly limited
in terms of the mode of use thereof as long as the compound represented
by the formula (1), optically active form thereof or a pharmaceutically
acceptable salt thereof and an agent for the prophylaxis or treatment of
autoimmune diseases such as rheumatism, systemic lupus erythematosus and
the like; sepsis; adult respiratory distress syndrome; chronic
obstructive pulmonary disease; allergic diseases such as asthma and the
like; atherosclerosis; cardiac infarction; brain infarction; psoriasis;
Alzheimer's disease; or serious organ injury (e.g., pneumonia, nephritis,
hepatitis, pancreatitis and the like) due to activation of leukocytes
caused by ischemia reperfusion, trauma, burn, surgical invasion and the
like are combined. For example, (A) the compound represented by the
formula (1), optically active form thereof or a pharmaceutically
acceptable salt thereof, and (B) an agent for the prophylaxis or
treatment of autoimmune diseases such as rheumatism, systemic lupus
erythematosus and the like; sepsis; adult respiratory distress syndrome;
chronic obstructive pulmonary disease; allergic diseases such as asthma
and the like; atherosclerosis; cardiac infarction; brain infarction;
psoriasis; Alzheimer's disease; or serious organ injury (e.g., pneumonia,
nephritis, hepatitis, pancreatitis and the like) due to activation of
leukocytes caused by ischemia reperfusion, trauma, burn, surgical
invasion and the like may be formulated as preparations to be each
generally administered, or a composition wherein they are combined in
advance may be used. The combined pharmaceutical drug of the present
invention may be, for example, a single agent obtained by mixing the
compound represented by the formula (1), optically active form thereof or
a pharmaceutically acceptable salt thereof and an agent for the
prophylaxis or treatment of autoimmune diseases such as rheumatism,
systemic lupus erythematosus and the like; sepsis; adult respiratory
distress syndrome; chronic obstructive pulmonary disease; allergic
diseases such as asthma and the like; atherosclerosis; cardiac
infarction; brain infarction; psoriasis; Alzheimer's disease; or serious
organ injury (e.g., pneumonia, nephritis, hepatitis, pancreatitis and the
like) due to activation of leukocytes caused by ischemia reperfusion,
trauma, burn, surgical invasion and the like according to a known
production method for pharmaceutical preparations using, where desired,
pharmaceutically acceptable diluent, excipient and the like, or
respective preparations thereof obtained using, where desired,
pharmaceutically acceptable diluent, excipient and the like, or a
combination preparation in a container including respective preparations
thereof (set, kit, pack). For example, the combined pharmaceutical drug
of the present invention can be used as a combination preparation
packaging the same or different preparations of a preparation containing
the compound represented by the formula (1), optically active form
thereof or a pharmaceutically acceptable salt thereof, and an agent for
the prophylaxis or treatment of autoimmune diseases such as rheumatism,
systemic lupus erythematosus and the like; sepsis; adult respiratory
distress syndrome; chronic obstructive pulmonary disease; allergic
diseases such as asthma and the like; atherosclerosis; cardiac
infarction; brain infarction; psoriasis; Alzheimer's disease; or serious
organ injury (e.g., pneumonia, nephritis, hepatitis, pancreatitis and the
like) due to activation of leukocytes caused by ischemia reperfusion,
trauma, burn surgical invasion and the like, or as a composition
containing the compound represented by the formula (1), optically active
form thereof or a pharmaceutically acceptable salt thereof and an agent
for the prophylaxis or treatment of autoimmune diseases such as
rheumatism, systemic lupus erythematosus and the like; sepsis; adult
respiratory distress syndrome; chronic obstructive pulmonary disease;
allergic diseases such as asthma and the like; atherosclerosis; cardiac
infarction; brain infarction; psoriasis; Alzheimer's disease; or serious
organ injury (e.g., pneumonia, nephritis, hepatitis, pancreatitis and the
like) due to activation of leukocytes caused by ischemia reperfusion,
trauma, burn surgical invasion and the like.

[0356]When the compound of the present invention, optically active form
thereof or a pharmaceutically acceptable salt thereof is used as a
combination composition, the ratio of the composition is optional, and
the amount of the compound of the present invention or a pharmaceutically
acceptable salt thereof to be mixed can be determined depending on the
kind of the various pharmaceutical agents to be mixed for combination,
and the factors such as titer and the like. When it is used as a
combination drug, the dose of the compound of the present invention or a
pharmaceutically acceptable salt thereof, and the pharmaceutical agent to
be combined therewith can be determined as appropriate from the range
generally employed. It is preferable to administer in a smaller dose than
the dose for single use of each pharmaceutical agent, in the hope of
affording a synergistic effect.

[0358]The present invention is specifically explained in the following by
referring to Preparation Examples, Examples, Formulation Examples and
Test Examples, which are not to be construed as limitative.

[0359]1H-NMR was measured at 300 MHz. The chemical shift of
1H-NMR was measured using tetramethylsilane (TMS) as the internal
standard and expressed as relative delta (δ) value in parts per
million (ppm). For the coupling constant, obvious multiplicity is shown
using s (singlet), d (doublet), t (triplet), q (quartet), sept (septet),
m (multiplet), dd (double doublet), brs (broad singlet) and the like in
hertz (Hz).

[0360]Thin-layer chromatography was manufactured by Merck, and column
chromatography was performed using silica gel manufactured by Fuji
silysia chemical.

Preparation Example 1

[0361]To a solution of 4-dimethylaminobenzaldehyde (11 g) in toluene (200
mL) were added 4-isopropylaniline (10 g) and molecular sieves 4A (20 g)
under ice-cooling, and the mixture was stirred at room temperature for
one day. The molecular sieves 4A was filtered off from the reaction
mixture, and the obtained filtrate was concentrated under reduced
pressure. The residue was dissolved in methanol (200 mL) and sodium
borohydride (2.3 g) was added under ice-cooling. The mixture was stirred
at room temperature for 5 hr. After methanol was distilled away, water
was added to the residue, and the mixture was extracted with chloroform.
The organic layer was washed with saturated brine and dried over
anhydrous sodium sulfate. The solvent was evaporated to give
(4-dimethylaminophenylmethyl)(4-isopropylphenyl)amine (13.6 g). melting
point: 71-73° C.

Preparation Example 2

[0362]By the reaction and treatment in the same manner as in Preparation
Example 1 using 4-dimethylaminobenzaldehyde (10.0 g) and 4-methoxyaniline
(8.25 g) as a starting material, (4-dimethylaminophenylmethyl)
(4-methoxyphenyl)amine (5 g) was obtained. melting point: 92-94°
C.

Preparation Example 3

[0363]To a solution of 1-ethylpyrazole-4-carboxylic acid (2.34 g) in
1,2-dichloroethane (50 mL) were added thionyl chloride (1.83 mL) and
several drops of DMF, and the mixture was stirred at 70° C. for
1.5 hr. The reaction mixture was concentrated under reduced pressure, and
methylene chloride (20 mL) was added to the residue. To this solution was
added a solution of 4-isopropylaniline (2.29 mL) in methylene chloride
(20 mL) under ice-cooling. The temperature of the mixture was raised to
room temperature and stirred at the same temperature for 1 hr. The
reaction mixture was added to saturated aqueous sodium hydrogencarbonate
and extracted with chloroform. The organic layer was washed with
saturated brine, and dried over anhydrous sodium sulfate. The solvent was
evaporated, and ether and hexane were added to the residue. The
precipitated solid was collected by filtration to give
N-(4-isopropylphenyl)-1-ethylpyrazole-4-carboxamide (3.76 g) (melting
point: 141.0° C.). To this compound (3.75 g) was added borane-THF
complex/1 mol/L-THF solution (BH3.THF complex/1M THF solution) (29
mL) and the mixture was heated under reflux for 4 hr. After cooling the
reaction mixture, 1 mol/L-hydrochloric acid (60 mL) was added, and the
mixture was stirred at room temperature for one day. The reaction mixture
was added to saturated aqueous sodium hydrogencarbonate and extracted
with chloroform. The organic layer was washed with saturated brine, and
dried over anhydrous sodium sulfate. The solvent was evaporated and the
residue was purified by silica gel column chromatography to give
[(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (1.95 g).

[0365]6-Chloronicotinic acid (3.15 g), 4-isopropylaniline (2.73 mL) and
triethylamine (5.6 mL) were dissolved in DMF (150 mL).
1-Hydroxybenzotriazole monohydrate (hereinafter to be abbreviated as
HOBt.H2O) (3.22 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
hydrochloride (hereinafter to be abbreviated as WSCI.HCl) (4.03 g) were
added under ice-cooling. The mixture was stirred at room temperature for
one day and the reaction mixture was partitioned between water and ethyl
acetate. The organic layer was washed with saturated brine, and dried
over anhydrous magnesium sulfate. The solvent was evaporated and ether
was added to the residue. The precipitated solid was collected by
filtration to give N-(4-isopropylphenyl)-6-chloropyridine-3-carboxamide
(4.72 g).

[0367]N-(4-Isopropylphenyl)-6-chloropyridine-3-carboxamide (1.00 g) was
dissolved in THF (10 mL) and sodium methoxide (0.21 g) was added. The
mixture was stirred at 50° C. for one day. After cooling, the
reaction mixture was partitioned between water and ethyl acetate. The
organic layer was washed with saturated brine and dried over anhydrous
magnesium sulfate. The solvent was evaporated and the residue was
purified by silica gel column chromatography to give
N-(4-isopropylphenyl)-6-methoxypyridine-3-carboxamide (0.76 g).

[0368]A BH3-THF complex/1M THF solution (6.3 mL) was added to
N-(4-isopropylphenyl)-6-methoxypyridine-3-carboxamide (0.76 g), and the
mixture was heated under reflux for 4 hr. After cooling the reaction
mixture, 1 mol/L hydrochloric acid (15 mL) was added and the mixture was
stirred at room temperature for one day. The reaction mixture was poured
into saturated aqueous sodium hydrogencarbonate and extracted with
chloroform. The organic layer was washed with saturated brine and dried
over anhydrous sodium sulfate. The solvent was evaporated and the residue
was purified by silica gel column chromatography to give
(4-isopropylphenyl)[(6-methoxypyridin-3-yl)methyl]amine (0.62 g).

[0370]To a solution of 7-methoxytetralone (22.3 g) in nitromethane (5 mL)
was added zinc iodide (0.65 g). While stirring the mixture,
trimethylsilyl cyanide (50 mL) was added under ice-cooling. The mixture
was stirred at room temperature for 1 hr, and the reaction mixture was
partitioned between water and chloroform. The organic layer was washed
with saturated brine and dried over anhydrous sodium sulfate. The solvent
was evaporated and the residue was dissolved in a mixed solvent of acetic
acid (200 mL) and conc. hydrochloric acid (200 mL). Thereto was added
stannous chloride (106 g) and the mixture was heated under reflux for one
day. After cooling, the reaction mixture was extracted with chloroform.
The organic layer was washed with saturated brine and dried over
anhydrous magnesium sulfate. The solvent was evaporated and ether was
added to the residue. The precipitated solid was collected by filtration
to give 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (8.1
g). melting point: 126-127° C.

Preparation Example 6

[0371]By the reaction and treatment in the same manner as in Preparation
Example 5 using 5-hydroxy-1-tetralone (20 g) as a starting material,
5-hydroxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (18.5 g) was
obtained. This compound (18.5 g) was dissolved in a mixed solvent of DMF
(105 mL) and toluene (42 mL). Thereto were added benzyl bromide (25.8 mL)
and potassium carbonate (54 g), and the mixture was stirred at
50-60° C. for 8 hr. The reaction mixture was partitioned between
water and ethyl acetate. The organic layer was washed with saturated
brine and dried over anhydrous magnesium sulfate. The solvent was
evaporated, and methanol (100 mL), 1,4-dioxane (100 mL) and 1 mol/L
aqueous sodium hydroxide solution (116 mL) were added to the residue. The
mixture was stirred at 50° C. for 5 hr. The reaction mixture was
partitioned between water and ethyl acetate, and the aqueous layer was
acidified with conc. hydrochloric acid. The mixture was extracted with
chloroform and dried over anhydrous magnesium sulfate. The solvent was
evaporated and the residue was purified by silica gel column
chromatography to give
5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (20.4 g).
melting point: 145-146° C.

Preparation Example 7

[0372]By the reaction and treatment in the same manner as in Preparation
Example 5 using 4-chromanone (5.1 g) as a starting material,
chroman-4-carboxylic acid (4.1 g) was obtained. melting point:
94.3° C.

Preparation Example 8

[0373]By the reaction and treatment in the same manner as in Preparation
Example 5 using 6-methoxy-4-chromanone (6.1 g) as a starting material,
6-methoxychroman-4-carboxylic acid (1.2 g) was obtained. melting point:
97.4° C.

Preparation Example 9

[0374]By the reaction and treatment in the same manner as in Preparation
Example 5 using 6-methoxy-1-indanone (5.6 g) as a starting material,
6-methoxyindan-1-carboxylic acid (2.6 g) was obtained. melting point:
101.1° C.

Preparation Example 10

[0375]By the reaction and treatment in the same manner as in Preparation
Example 6 using 4-hydroxy-1-indanone (5 g) as a starting material,
4-benzyloxyindan-1-carboxylic acid (1.4 g) was obtained. melting point:
133.4° C.

Preparation Example 11

[0376]To a solution of 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (2
g) in methylene chloride (10 mL) was added thionyl chloride (1 mL) and
the mixture was heated under reflux with stirring for 3 hr. The reaction
mixture was concentrated under reduced pressure, and THF (5 mL) was added
to the residue. This solution was added to a solution of
4-isopropylaniline (1.53 g) and triethylamine (4.6 mL) in THF (10 mL)
under ice-cooling. The temperature was raised to room temperature, and
the mixture was stirred at the same temperature for 1 hr. The reaction
mixture was partitioned between water and ethyl acetate. The organic
layer was washed with saturated brine and dried over anhydrous magnesium
sulfate. The solvent was evaporated and hexane was added to the residue.
The precipitated solid was collected by filtration to give
N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (2.78
g). melting point: 163.1° C.

Preparation Example 12

[0377]7-Methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.62 g),
4-isopropylaniline (0.41 g) and triethylamine (0.84 mL) were dissolved in
DMF (20 mL), and HOBt.H2O (0.48 g) and WSCI.HCl (0.61 g) were added
under ice-cooling. The mixture was stirred at room temperature for one
day and the reaction mixture was partitioned between water and ethyl
acetate. The organic layer was washed with saturated brine and dried over
anhydrous magnesium sulfate. The solvent was evaporated and ether was
added to the residue. The precipitated solid was collected by filtration
to give N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-c-
arboxamide (0.70 g). melting point: 168-169° C.

Preparation Example 13

[0378]To a solution of ethyl pyrazole-4-carboxylate (13.0 g),
4-dimethylaminopyridine (0.57 g) and triethylamine (15.5 mL) in
tetrahydrofuran (80 mL) was added a solution of di-tert-butyl dicarbonate
(24.3 g) in tetrahydrofuran (20 mL) at room temperature. The mixture was
stirred at the same temperature for 4 hr. The reaction mixture was
concentrated under reduced pressure, and the residue was partitioned
between water and ethyl acetate. The organic layer was washed with
saturated brine and dried over anhydrous magnesium sulfate. The solvent
was evaporated and the residue was purified by silica gel column
chromatography to give ethyl
1-(tert-butyloxycarbonyl)pyrazole-4-carboxylate (22.1 g).

[0380]Ethyl (1-tert-butyloxycarbonyl)pyrazole-4-carboxylate (17.0 g) was
dissolved in anhydrous tetrahydrofuran (150 mL), and 1 mol/L
diisobutylaluminum hydride/toluene solution (142 mL) was added at
-78° C. over 40 min. The reaction temperature was raised to
0° C. over 1.5 hr, and methanol-ether (1:9) (100 mL), saturated
aqueous potassium sodium tartrate tetrahydrate (Rochelle salt) solution
(70 mL), water (330 mL) and ether (1 L) were successively added to the
reaction mixture at the same temperature. The mixture was stirred for one
more hour. The reaction mixture was passed through Celite, and the
filtrate was washed with saturated brine and dried over anhydrous sodium
sulfate. The solvent was evaporated, and the residue was purified by
silica gel column chromatography to give
1-(tert-butyloxycarbonyl)-4-(hydroxymethyl)pyrazole (5.92 g).

[0382]By the reaction and treatment in the same manner as in Preparation
Example 11 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic
acid (5.48 g) and 4-isopropylaniline (3.90 mL) as starting materials,
5-benzyloxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxa-
mide (5.94 g) was obtained. melting point: 170.4° C.

Preparation Example 15

[0383]By the reaction and treatment in the same manner as in Preparation
Example 11 using 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.51 g)
and 5-amino-2-isopropylpyridine (1.17 g) as starting materials,
N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide
(2.18 g) was obtained. melting point: 155.7° C.

Preparation Example 16

[0384]By the reaction and treatment in the same manner as in Preparation
Example 11 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic
acid (1.06 g) and 5-amino-2-isopropylpyridine (0.50 g) as starting
materials,
5-benzyloxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-c-
arboxamide (1.08 g) was obtained. melting point: 157.4° C.

Preparation Example 17

[0385]By the reaction and treatment in the same manner as in Preparation
Example 11 using
5-benzyloxy-8-fluoro-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid
(2.30 g) and 5-amino-2-isopropylpyridine (1.04 g) as starting materials,
5-benzyloxy-8-fluoro-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphth-
alene-1-carboxamide (2.83 g) was obtained. melting point: 184.0° C.

Preparation Example 18

[0386]To a solution of 8-nitrochroman-4-carboxylic acid (3.0 g) and
4-isopropylaniline (2.0 g) in dimethylformamide (30 mL) were added
N-hydroxybenzotriazole hydrate (2.0 g) and
1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (2.8 g), and
the mixture was stirred at room temperature. After the completion of the
reaction, the reaction mixture was partitioned between water and ethyl
acetate. The organic layer was washed with saturated brine and dried over
magnesium sulfate. The solvent was evaporated, and the residue was
purified by silica gel column chromatography to give
N-(4-isopropylphenyl)-8-nitrochroman-4-carboxamide (4.1 g).

[0390]By the reaction and treatment in the same manner as in Preparation
Example 18 using
5-benzyloxy-8-methyl-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid
(1.34 g) and 5-amino-2-isopropylpyridine (0.62 g) as starting materials,
5-benzyloxy-N-(6-isopropylpyridin-3-yl)-8-methyl-1,2,3,4-tetrahydronaphth-
alene-1-carboxamide (1.75 g) was obtained.

[0392]By the reaction and treatment in the same manner as in Preparation
Example 18 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic
acid (20.0 g) and 5-amino-2-methoxypyridine (8.72 g), as starting
materials,
5-benzyloxy-N-(6-methoxypyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-car-
boxamide (23.9 g) was obtained.

[0394]7-Methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (5.0 g)
and (R)-(+)-1-phenethylamine (3.13 mL) were dissolved in methanol (50
mL), and the solvent was evaporated under reduced pressure to give crude
crystals (7.33 g). This was recrystallized from a mixed solvent of
methanol and isopropyl ether. The obtained crystals were partitioned
between ethyl acetate and 1 mol/L-hydrochloric acid. The organic layer
was washed with saturated brine and dried over magnesium sulfate.

[0402]7-Methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (5.0 g)
and (S)-(-)-1-phenethylamine (3.2 mL) were dissolved in methanol (50 mL),
and the solvent was evaporated under reduced pressure to give crude
crystals (7.33 g). This was recrystallized from a mixed solvent of
methanol and isopropyl ether. The obtained crystals were partitioned
between ethyl acetate and 1 mol/L-hydrochloric acid. The organic layer
was washed with saturated brine and dried over magnesium sulfate. The
solvent was evaporated under reduced pressure to give
(S)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.96 g).

[0403]optical purity>99.9% e.e.

Analysis Conditions

[0404]column: CHIRALCEL OD (DAICEL)

[0405]developing solvent: hexane/isopropanol/acetic acid=97/3/3

[0406]flow rate: 0.5 mL/min

[0407]UV detection: 254 nm

[0408]retention time: 26 min

Preparation Example 24

[0409]By the reaction and treatment in the same manner as in Preparation
Example 11 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic
acid (2.82 g) and 2-amino-5-methylpyridine (1.08 g) as starting
materials,
5-benzyloxy-N-(5-methylpyridin-2-yl)-1,2,3,4-tetrahydronaphthalene-1-carb-
oxamide (2.00 g) was obtained.

[0410]MS (ESI) m/z: 373 [MH].sup.+

Example 1

##STR00020##

[0412]To a solution of 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid
(1.0 g) in methylene chloride (10 mL) was added thionyl chloride (0.68
mL), and the mixture was heated under reflux with stirring for 3 hr. The
reaction mixture was concentrated under reduced pressure, and THF (6 mL)
was added to the residue. This solution was added to a solution of
[(4-dimethylaminophenyl)methyl](4-ethylphenyl)-amine (1.2 g) and
triethylamine (2 mL) in THF (6 mL) under ice-cooling. The mixture was
allowed to warm to room temperature and stirred at the same temperature
for one day. The reaction mixture was partitioned between water and ethyl
acetate. The organic layer was washed with saturated brine and dried over
anhydrous magnesium sulfate. The solvent was evaporated, and the residue
was purified by silica gel column chromatography. The obtained crystals
were recrystallized from a mixed solvent of ethyl acetate and hexane to
give N-[(4-dimethylaminophenyl)methyl]-N-(4-ethylphenyl)-1,2,3,4-tetrahyd-
ronaphthalene-1-carboxamide (0.28 g). melting point: 109-110° C.

Example 2

##STR00021##

[0414]By the reaction and treatment in the same manner as in Example 1
using indan-1-carboxylic acid (0.46 g) and
[(4-dimethylaminophenyl)methyl](4-ethylphenyl)amine (0.6 g) as starting
materials, N-[(4-dimethylaminophenyl)
methyl]-N-(4-ethylphenyl)indan-1-carboxamide (0.15 g) was obtained.

[0417]By the reaction and treatment in the same manner as in Example 1
using 6,7,8,9-tetrahydro-5H-benzocycloheptene-5-carboxylic acid (0.54 g)
and [(4-dimethylaminophenyl)methyl](4-ethylphenyl)amine (0.6 g) as
starting materials,
N-[(4-dimethylaminophenyl)methyl]-N-(4-ethylphenyl)-6,7,8,9-tetrahydro-5H-
-benzocycloheptene-5-carboxamide (0.2 g) was obtained.

[0420]To a solution of 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid
(3.3 g) in 1,2-dichloroethane (20 mL) was added thionyl chloride (2.1
mL), and the mixture was heated under reflux with stirring for 3 hr. The
reaction mixture was concentrated under reduced pressure, and methylene
chloride (10 mL) was added to the residue. This solution was added to a
solution of [(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (5.1
g) in methylene chloride (10 mL) under ice-cooling. The reaction mixture
was warmed to room temperature and stirred at the same temperature for
one day. The reaction mixture was partitioned between water and ethyl
acetate. The organic layer was washed with saturated brine and dried over
anhydrous magnesium sulfate. The solvent was evaporated, and the residue
was purified by silica gel column chromatography. The obtained crystals
were recrystallized from isopropyl ether to give
N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydr-
onaphthalene-1-carboxamide (4.38 g) melting point: 121° C.

Example 5

##STR00024##

[0422]To a solution of 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid
(0.24 g) in methylene chloride (3 mL) was added thionyl chloride (0.15
mL), and the mixture was heated under reflux with stirring for 3 hr. The
reaction mixture was concentrated under reduced pressure, and THF (2 mL)
was added to the residue. This solution was added to a solution of
(5-bromo-2-isobutoxyphenyl)[(4-dimethylaminophenyl)methyl]amine (0.5 g)
and sodium hydride (0.07 g) in THF (3 mL). The reaction mixture was
warmed to room temperature and stirred at the same temperature for one
day. The reaction mixture was partitioned between water and ethyl
acetate. The organic layer was washed with saturated brine and dried over
anhydrous magnesium sulfate. The solvent was evaporated, and the residue
was purified by silica gel column chromatography. The obtained crystals
were recrystallized from ethyl acetate to give
N-(5-bromo-2-isobutoxyphenyl)-N-[(4-dimethylaminophenyl)methyl]-1,2,3,4-t-
etrahydronaphthalene-1-carboxamide (0.3 g). melting point: 176-178°
C.

Example 6

##STR00025##

[0424]N-(4-Isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide
(0.5 g) and butyl bromide (0.22 mL) were dissolved in DMF (3 mL), and
sodium hydride (0.08 g) was added under ice-cooling. The mixture was
stirred at the same temperature for 30 min and then at room temperature
for 3 hr. The reaction mixture was partitioned between water and ethyl
acetate. The organic layer was washed with saturated brine and dried over
anhydrous magnesium sulfate. The solvent was evaporated and the residue
was purified by silica gel column chromatography to give
N-butyl-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide
(0.53 g).

[0427]By the reaction and treatment in the same manner as in Example 6
using N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide
(0.5 g) and 2-morpholino-2-oxoethyl chloride (0.33 g) as starting
materials,
N-(4-isopropylphenyl)-N-(2-morpholino-2-oxoethyl)-1,2,3,4-tetrahydronapht-
halene-1-carboxamide (0.43 g) was obtained. melting point: 180° C.

Example 8

##STR00027##

[0429]By the reaction and treatment in the same manner as in Example 6
using N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide
(0.75 g) and 3-(tetrahydropyran-2-yloxy)propyl bromide (0.52 mL) as
starting materials,
N-(4-isopropylphenyl)-N-[3-(tetrahydropyran-2-yloxy)propyl]-1,2,3,4-tetra-
hydronaphthalene-1-carboxamide (0.9 g) was obtained.

[0432]N-(4-Isopropylphenyl)-N-[3-(tetrahydropyran-2-yloxy)propyl]-1,2,3,4--
tetrahydronaphthalene-1-carboxamide (0.24 g) was dissolved in a mixed
solvent (7 mL) of acetic acid: THF: water (4:2:1) and stirred at room
temperature for 2 hr. The reaction mixture was partitioned between water
and ethyl acetate. The organic layer was washed with saturated brine and
dried over anhydrous magnesium sulfate. The solvent was evaporated, and
the residue was purified by silica gel column chromatography to give
N-(3-hydroxypropyl)-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-
-carboxamide (0.12 g).

[0435]By the reaction and treatment in the same manner as in Example 1
using thiochroman-4-carboxylic acid (0.55 g) and
[(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.63 g) as
starting materials,
N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)thiochroman-4-carb-
oxamide (0.3 g) was obtained. melting point: 118° C.

Example 11

##STR00030##

[0437]By the reaction and treatment in the same manner as in Example 1
using 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.56 g)
and (3-cyanopropyl) (4-isopropylphenyl)amine (1.79 g) as starting
materials,
N-(3-cyanopropyl)-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronapht-
halene-1-carboxamide (1.56 g) was obtained. melting point: 74-750°
C.

Example 12

##STR00031##

[0439]To a solution of
7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.0 g) in
1,2-dichloroethane (20 mL) was added thionyl chloride (2.1 mL), and the
mixture was heated under reflux with stirring for 3 hr. The reaction
mixture was concentrated under reduced pressure, and methylene chloride
(10 mL) was added to the residue. This solution was added to a solution
of [(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (1.3 g) in
methylene chloride (10 mL) under ice-cooling. The reaction mixture was
warmed to room temperature and stirred at the same temperature for one
day. The reaction mixture was partitioned between water and ethyl
acetate. The organic layer was washed with saturated brine and dried over
anhydrous magnesium sulfate. The solvent was evaporated, and the residue
was purified by silica gel column chromatography to give
N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-
-tetrahydronaphthalene-1-carboxamide (0.73 g).

[0442]By the reaction and treatment in the same manner as in Example 1
using chroman-4-carboxylic acid (0.5 g) and
[(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.63 g) as
starting materials, N-[(4-dimethylaminophenyl)
methyl]-N-(4-isopropylphenyl)chroman-4-carboxamide (0.25 g) was obtained.
melting point: 110-112° C.

Example 14

##STR00033##

[0444]By the reaction and treatment in the same manner as in Example 1
using 1,1-dioxothiochroman-4-carboxylic acid (0.26 g) and
[(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.31 g) as
starting materials, N-[(4-dimethylaminophenyl)
methyl]-N-(4-isopropylphenyl)-1,1-dioxothiochroman-4-carboxamide (0.07 g)
was obtained. melting point: 185-187° C.

Example 15

##STR00034##

[0446]By the reaction and treatment in the same manner as in Example 12
using 5-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (2.0 g)
and [(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (1.91 g) as
starting materials,
N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-5-methoxy-1,2,3,4-
-tetrahydronaphthalene-1-carboxamide (0.48 g) was obtained.

[0449]By the reaction and treatment in the same manner as in Example 12
using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (2.0 g)
and [(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (1.91 g) as
starting materials,
5-benzyloxy-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-1,2,3-
,4-tetrahydronaphthalene-1-carboxamide (0.76 g) was obtained.

[0452]5-Benzyloxy-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)--
1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.75 g) was dissolved in
methanol (60 mL), and 10% palladium carbon (0.5 g) and ammonium formate
(1.5 g) were added. The mixture was stirred at room temperature for one
day. The reaction mixture was filtrated, and the filtrate was
concentrated. Water was added to the residue, and the precipitated crude
crystals were recrystallized from ethyl acetate to give
N-[(4-dimethylaminophenyl)methyl]-5-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-
-tetrahydronaphthalene-1-carboxamide (0.5 g). melting point:
200-202° C.

Example 18

##STR00037##

[0454]By the reaction and treatment in the same manner as in Example 1
using 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.1 g) and
(4-isopropylphenyl)[6-(tetrahydropyran-2-yloxy)hexyl]amine (2.0 g) as
starting materials,
N-(4-isopropylphenyl)-N-[6-(tetrahydropyran-2-yloxy)hexyl]-1,2,3,4-tetrah-
ydronaphthalene-1-carboxamide (1.0 g) was obtained. By the reaction and
treatment of this compound in the same manner as in Example 9,
N-(6-hydroxyhexyl)-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1--
carboxamide (0.64 g) was obtained.

[0457]By the reaction and treatment in the same manner as in Example 1
using 2-oxo-1,2,3,4-tetrahydroquinoline-4-carboxylic acid (0.5 g) and
[(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.7 g) as
starting materials,
N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-2-oxo-1,2,3,4-tet-
rahydroquinoline-4-carboxamide (0.6 g) was obtained. melting point:
170° C.

Example 20

##STR00039##

[0459]N-[(4-Dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,-
2,3,4-tetrahydronaphthalene-1-carboxamide (3.2 g) was dissolved in
methylene chloride (60 mL), and boron tribromide (0.72 mL) was added
under ice-cooling. The mixture was stirred at room temperature for one
day. The reaction mixture was partitioned between saturated aqueous
sodium hydrogencarbonate and chloroform. The organic layer was washed
with saturated brine and dried over anhydrous magnesium sulfate. The
solvent was evaporated, and the residue was purified by silica gel column
chromatography to give
N-[(4-dimethylaminophenyl)methyl]-7-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-
-tetrahydronaphthalene-1-carboxamide (0.36 g). melting point:
214-217° C.

Example 21

##STR00040##

[0461]By the reaction and treatment in the same manner as in Example 12
using 6-methoxyindan-1-carboxylic acid (0.5 g) and
[(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.7 g) as
starting materials,
N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-6-methoxyindan-1--
carboxamide (0.53 g) was obtained.

[0464]By the reaction and treatment in the same manner as in Example 1
using 7-isopropyl-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.0 g)
and [(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (1.07 g) as
starting materials,
N-[(4-dimethylaminophenyl)methyl]-7-isopropyl-N-(4-isopropylphenyl)-1,2,3-
,4-tetrahydronaphthalene-1-carboxamide (0.53 g) was obtained. melting
point: 123-125° C.

Example 23

##STR00042##

[0466]By the reaction and treatment in the same manner as in Example 1
using 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.5 g) and
[(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.57 g) as
starting materials,
N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydron-
aphthalene-1-carboxamide (0.12 g) was obtained. melting point:
75-76° C.

Example 24

##STR00043##

[0468]By the reaction and treatment in the same manner as in Example 12
using 6-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.54 g)
and [(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.7 g) as
starting materials,
N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-6-methoxy-1,2,3,4-
-tetrahydronaphthalene-1-carboxamide (0.36 g) was obtained.

[0471]By the reaction and treatment in the same manner as in Example 1
using 6-methoxychroman-4-carboxylic acid (0.54 g) and
[(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.7 g) as
starting materials, N-[(4-dimethylaminophenyl)
methyl]-N-(4-isopropylphenyl)-6-methoxychroman-4-carboxamide (0.3 g) was
obtained. melting point: 82-84° C.

Example 26

##STR00045##

[0473]By the reaction and treatment in the same manner as in Example 12
using 7-methyl-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.0 g)
and [(4-dimethylaminophenyl)methyl](4-isopropylphenyl) amine (1.40 g) as
starting materials,
N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-7-methyl-1,2,3,4--
tetrahydronaphthalene-1-carboxamide (0.53 g) was obtained.

[0490]By the reaction and treatment in the same manner as in Example 12
using 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.5 g)
and (4-isopropylphenyl)[(4-methylthiophenyl)methyl]amine (2.0 g) as
starting materials,
N-(4-isopropylphenyl)-7-methoxy-N-[(4-methylthiophenyl)methyl]-1,2,3,4-te-
trahydronaphthalene-1-carboxamide (1.4 g) was obtained.

[0493]N-(4-Isopropylphenyl)-7-methoxy-N-[(4-methylthiophenyl)methyl]-1,2,3-
,4-tetrahydronaphthalene-1-carboxamide (1.0 g) was dissolved in acetic
acid (10 mL), and 30% aqueous hydrogen peroxide (5.5 mL) was added at
room temperature. The mixture was stirred with heating at 100° C.
for 3 hr. Water was added to the reaction mixture, and the precipitated
solid was purified by silica gel column chromatography to give crude
crystals. The crystals were recrystallized from ethyl acetate to give
N-(4-isopropylphenyl)-N-[(4-methylsulfonylphenyl)methyl]-7-methoxy-1,2,3,-
4-tetrahydronaphthalene-1-carboxamide (0.61 g). melting point:
131-132° C.

Example 36

##STR00055##

[0495]By the reaction and treatment in the same manner as in Example 1
using 6-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.1 g)
and [(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (1.05 g) as
starting materials,
6-benzyloxy-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-1,2,3-
,4-tetrahydronaphthalene-1-carboxamide (0.23 g) was obtained. melting
point: 107-109° C.

Example 37

##STR00056##

[0497]To a solution of
6-benzyloxy-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-1,2,3-
,4-tetrahydronaphthalene-1-carboxamide (0.75 g) in methanol (8.6 mL) were
added 10% palladium-carbon (0.09 g) and ammonium formate (0.44 g), and
the mixture was stirred at room temperature for 24 hr. The reaction
mixture was filtrated, and the solvent was evaporated. The obtained crude
crystals were recrystallized from a mixed solvent of ethyl acetate and
hexane to give
N-[(4-dimethylaminophenyl)methyl]-6-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-
-tetrahydronaphthalene-1-carboxamide (0.23 g). melting point:
169-171° C.

Example 38

##STR00057##

[0499]By the reaction and treatment in the same manner as in Example 12
using 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.45 g) and
(4-butylphenyl)[(4-dimethylaminophenyl)-methyl]amine (0.6 g) as starting
materials,
N-(4-butylphenyl)-N-[(4-dimethylaminophenyl)methyl]-1,2,3,4-tetrahydronap-
hthalene-1-carboxamide (0.35 g) was obtained.

[0502]By the reaction and treatment in the same manner as in Example 12
using 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.75 g)
and [(1,3-dioxaindan-5-yl)methyl](4-methoxyphenyl)amine (0.93 g) as
starting materials,
N-[(1,3-dioxaindan-5-yl)methyl]-N-(4-methoxyphenyl)-7-methoxy-1,2,3,4-tet-
rahydronaphthalene-1-carboxamide (0.15 g) was obtained.

[0505]By the reaction and treatment in the same manner as in Example 1
using 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.5 g)
and [(4-methoxyphenyl)methyl](4-methoxyphenyl)amine (0.88 g) as starting
materials,
N-[(4-methoxyphenyl)methyl]-N-(4-methoxyphenyl)-7-methoxy-1,2,3,4-tetrahy-
dronaphthalene-1-carboxamide (0.72 g) was obtained. melting point:
89-90° C.

Example 41

##STR00060##

[0507]By the reaction and treatment in the same manner as in Example 12
using 6-chlorochroman-4-carboxylic acid (0.66 g) and
[(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.83 g) as
starting materials,
6-chloro-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)chroman-4-
-carboxamide (0.36 g) was obtained.

[0510]By the reaction and treatment in the same manner as in Example 12
using 6-bromochroman-4-carboxylic acid (0.54 g) and
[(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.57 g) as
starting materials,
6-bromo-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)chroman-4--
carboxamide (0.52 g) was obtained.

[0513]By the reaction and treatment in the same manner as in Example 12
using 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.31 g)
and (4-isopropylphenyl)[(6-isopropylpyridin-3-yl)methyl]amine (0.46 g) as
starting materials,
N-(4-isopropylphenyl)-N-[(6-isopropylpyridin-3-yl)methyl]-7-methoxy-1,2,3-
,4-tetrahydronaphthalene-1-carboxamide (0.12 g) was obtained.

[0516]By the reaction and treatment in the same manner as in Example 12
using 8-methoxychroman-4-carboxylic acid, (0.64 g) and
[(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.83 g) as
starting materials,
N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-8-methoxychroman--
4-carboxamide (0.69 g) was obtained.

[0519]By the reaction and treatment in the same manner as in Example 12
using 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.70 g) and
[(4-methoxyphenyl)methyl](4-methoxyphenyl)amine (0.97 g) as starting
materials,
N-[(4-methoxyphenyl)methyl]-N-(4-methoxyphenyl)-1,2,3,4-tetrahydronaphtha-
lene-1-carboxamide (1.33 g) was obtained.

[0522]By the reaction and treatment in the same manner as in Example 12
using 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.50 g)
and (4-isopropylphenyl)[(6-methoxypyridin-3-yl)methyl]amine (0.62 g) as
starting materials,
N-(4-isopropylphenyl)-N-[(6-methoxypyridin-3-yl)methyl]-7-methoxy-1,2,3,4-
-tetrahydronaphthalene-1-carboxamide was obtained. This was dissolved in
ether, and 4N-hydrochloric acid/dioxane was added. The precipitated solid
was collected by filtration to give
N-(4-isopropylphenyl)-N-[(6-methoxypyridin-3-yl)methyl]-7-methoxy-1,2,3,4-
-tetrahydronaphthalene-1-carboxamide monohydrochloride (0.47 g).

[0523]melting point: 114-117° C.

Example 47

##STR00066##

[0525]By the reaction and treatment in the same manner as in Example 12
using 4-methoxyindan-1-carboxylic acid (0.20 g) and
[(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.27 g) as
starting materials,
N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-4-methoxyindan-1--
carboxamide (0.24 g) was obtained.

[0528]By the reaction and treatment in the same manner as in Example 12
using 5-methoxyindan-1-carboxylic acid (0.50 g) and
[(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.80 g) as
starting materials,
N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-5-methoxyindan-1--
carboxamide (1.00 g) was obtained.

[0531]By the reaction and treatment in the same manner as in Example 12
using 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.5 g)
and [(1-benzylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (2.22 g) as
starting materials,
N-[(1-benzylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4--
tetrahydronaphthalene-1-carboxamide (1.64 g) was obtained.

[0534]By the reaction and treatment in the same manner as in Example 4
using 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.31 g)
and (4-isopropylphenyl)[(4-methoxyphenyl)methyl]amine (0.38 g) as
starting materials,
N-(4-isopropylphenyl)-N-[(4-methoxyphenyl)methyl]-7-methoxy-1,2,3,4-tetra-
hydronaphthalene-1-carboxamide (0.37 g) was obtained. melting point:
83-85° C.

Example 51

##STR00070##

[0536]By the reaction and treatment in the same manner as in Example 12
using 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.58 g)
and [(6-ethylpyridin-3-yl)methyl](4-isopropylphenyl)amine (0.71 g) as
starting materials,
N-[(6-ethylpyridin-3-yl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-t-
etrahydronaphthalene-1-carboxamide (0.69 g) was obtained.

[0539]By the reaction and treatment in the same manner as in Example 12
using 4-benzyloxyindan-1-carboxylic acid (0.7 g) and
[(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.7 g) as
starting materials,
4-benzyloxy-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)indan--
1-carboxamide (1.5 g) was obtained.

[0542]By the reaction and treatment in the same manner as in Example 37
using 4-benzyloxy-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-
indan-1-carboxamide (1.19 g) as a starting material,
N-[(4-dimethylaminophenyl)methyl]-4-hydroxy-N-(4-isopropylphenyl)indan-1--
carboxamide (0.57 g) was obtained. melting point: 158-160° C.

Example 54

##STR00073##

[0544]To a solution of
N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydr-
onaphthalene-1-carboxamide (0.79 g) in toluene (10 mL) was added
Lawesson's reagent (0.9 g), and the mixture was heated under reflux for 5
hr. The reaction mixture was partitioned between water and ethyl acetate.
The organic layer was washed with saturated brine and dried over
anhydrous magnesium sulfate. The solvent was evaporated, and the residue
was purified by silica gel column chromatography to give
N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydr-
onaphthalene-1-carbothioamide (0.19 g). melting point: 123-125° C.

Example 55

##STR00074##

[0546]By the reaction and treatment in the same manner as in Example 12
using 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.31 g)
and [(6-dimethylaminopyridin-3-yl)methyl](4-isopropylphenyl)amine (0.24
g) as starting materials,
N-[(6-dimethylaminopyridin-3-yl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1-
,2,3,4-tetrahydronaphthalene-1-carboxamide was obtained. This was
dissolved in ether, and 4 mol/L-hydrochloric acid/dioxane (0.30 mL) was
added. The solvent was evaporated. The obtained crude crystals were
recrystallized from ethyl acetate-hexane to give
N-[(6-dimethylaminopyridin-3-yl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1-
,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride 1/2 hydrate (0.43
g). melting point: 158-160° C.

Example 56

##STR00075##

[0548]By the reaction and treatment in the same manner as in Example 12
using 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.31 g)
and (4-isopropylphenyl)[(5-methoxypyridin-2-yl)methyl]amine (0.38 g) as
starting materials,
N-(4-isopropylphenyl)-N-[(5-methoxypyridin-2-yl)methyl]-7-methoxy-1,2,3,4-
-tetrahydronaphthalene-1-carboxamide was obtained. This is dissolved in
ether, and 4 mol/L-hydrochloric acid/dioxane (0.40 mL) was added. The
solvent was evaporated, and ether was added to the residue. The
precipitated crystals were collected by filtration to give
N-(4-isopropylphenyl)-N-[(5-methoxypyridin-2-yl)methyl]-7-methoxy-1,2,3,4-
-tetrahydronaphthalene-1-carboxamide hydrochloride 1/2 hydrate (0.54 g).
melting point: 108-110° C.

Example 57

##STR00076##

[0550]By the reaction and treatment in the same manner as in Example 4
using 6-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.31 g)
and [(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.37 g) as
starting materials,
N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-6-methoxy-1,2,3,4-t-
etrahydronaphthalene-1-carboxamide (0.45 g) was obtained. melting point:
111-113° C.

Example 58

##STR00077##

[0552]By the reaction and treatment in the same manner as in Example 12
using 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.31 g)
and [(2-dimethylaminopyridin-3-yl)methyl](4-isopropylphenyl)amine (0.40
g) as starting materials,
N-[(2-dimethylaminopyridin-3-yl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1-
,2,3,4-tetrahydronaphthalene-1-carboxamide (0.58 g) was obtained.

[0555]By the reaction and treatment in the same manner as in Example 12
using 5-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.31 g)
and [(1-ethylpyrazol-4-yl)methyl] (4-isopropylphenyl)amine (0.37 g) as
starting materials,
N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-5-methoxy-1,2,3,4-t-
etrahydronaphthalene-1-carboxamide (0.52 g) was obtained.

[0558]By the reaction and treatment in the same manner as in Example 12
using 6-methoxyindan-1-carboxylic acid (0.29 g) and
[(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.37 g) as
starting materials,
N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-6-methoxyindan-1-ca-
rboxamide (0.35 g) was obtained.

[0561]By the reaction and treatment in the same manner as in Example 12
using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.56
g) and [(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.49 g) as
starting materials,
5-benzyloxy-N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-
-tetrahydronaphthalene-1-carboxamide (0.72 g) was obtained.

[0563]By the reaction and treatment in the same manner as in Example 37
using 5-benzyloxy-N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-1-
,2,3,4-tetrahydronaphthalene-1-carboxamide (0.72 g),
N-[(1-ethylpyrazol-4-yl)methyl]-5-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-t-
etrahydronaphthalene-1-carboxamide (0.33 g) was obtained. melting point:
212-215° C.

Example 62

##STR00081##

[0565]By the reaction and treatment in the same manner as in Example 6
using N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-car-
boxamide (0.49 g) and 1-methanesulfonyloxy-2-(4-methoxyphenyl)ethane (0.38
g) as starting materials,
N-(4-isopropylphenyl)-N-[2-(4-methoxyphenyl)ethyl]-7-methoxy-1,2,3,4-tetr-
ahydronaphthalene-1-carboxamide (0.15 g) was obtained.

[0568]By the reaction and treatment in the same manner as in Example 6
using N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-car-
boxamide (0.49 g) and 1-methanesulfonyloxy-3-(4-methoxyphenyl)propane
(0.40 g) as starting materials,
N-(4-isopropylphenyl)-N-[3-(4-methoxyphenyl)propyl]-7-methoxy-1,2,3,4-tet-
rahydronaphthalene-1-carboxamide (0.41 g) was obtained.

[0571]By the reaction and treatment in the same manner as in Example 6
using N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-car-
boxamide (0.49 g) and 1-methanesulfonyloxy-4-(4-methoxyphenyl)butane (0.43
g) as starting materials,
N-(4-isopropylphenyl)-N-[4-(4-methoxyphenyl)butyl]-7-methoxy-1,2,3,4-tetr-
ahydronaphthalene-1-carboxamide (0.25 g) was obtained.

[0574]By the reaction and treatment in the same manner as in Example 4
using 7-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.56
g) and [(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.49 g) as
starting materials,
7-benzyloxy-N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-
-tetrahydronaphthalene-1-carboxamide (0.61 g) was obtained. melting point:
100-101° C.

Example 66

##STR00085##

[0576]By the reaction and treatment in the same manner as in Example 4
using 4-benzyloxyindan-1-carboxylic acid (0.54 g) and
[(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.49 g) as
starting materials,
4-benzyloxy-N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)indan-1--
carboxamide (0.79 g) was obtained.

[0579]By the reaction and treatment in the same manner as in Example 4
using indan-1-carboxylic acid (0.24 g) and
[(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.37 g) as
starting materials,
N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)indan-1-carboxamide
(0.23 g) was obtained. melting point: 83-84° C.

Example 68

##STR00087##

[0581]By the reaction and treatment in the same manner as in Example 4
using 6-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.56
g) and [(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.49 g) as
starting materials,
6-benzyloxy-N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-
-tetrahydronaphthalene-1-carboxamide (0.65 g) was obtained. melting point:
122-124° C.

Example 69

##STR00088##

[0583]By the reaction and treatment in the same manner as in Example 12
using 6-fluorochroman-4-carboxylic acid (0.29 g) and
[(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.37 g) as
starting materials,
N-[(1-ethylpyrazol-4-yl)methyl]-6-fluoro-N-(4-isopropylphenyl)chroman-4-c-
arboxamide (0.42 g) was obtained.

[0586]By the reaction and treatment in the same manner as in Example 12
using 6,7,8,9-tetrahydro-5H-benzocycloheptene-5-carboxylic acid (0.29 g)
and [(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.37 g) as
starting materials,
N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-6,7,8,9-tetrahydro--
5H-benzocycloheptene-5-carboxamide (0.36 g) was obtained.

[0589]By the reaction and treatment in the same manner as in Example 12
using chroman-4-carboxylic acid (0.27 g) and
[(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.37 g) as
starting materials,
N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)chroman-4-carboxamid-
e (0.52 g) was obtained.

[0592]By the reaction and treatment in the same manner as in Example 12
using 6-methoxychroman-4-carboxylic acid (0.31 g) and
[(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.37 g) as
starting materials,
N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-6-methoxychroman-4--
carboxamide (0.39 g) was obtained.

[0595]By the reaction and treatment in the same manner as in Example 12
using 7-isopropyl-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.33
g) and [(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.37 g) as
starting materials,
N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-7-isopropyl-1,2,3,4-
-tetrahydronaphthalene-1-carboxamide (0.46 g) was obtained.

[0598]By the reaction and treatment in the same manner as in Example 4
using 7-methyl-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.29 g)
and [(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.37 g) as
starting materials,
N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-7-methyl-1,2,3,4-te-
trahydronaphthalene-1-carboxamide (0.41 g) was obtained. melting point:
110-112° C.

Example 75

##STR00094##

[0600]By the reaction and treatment in the same manner as in Example 37
using 7-benzyloxy-N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-1-
,2,3,4-tetrahydronaphthalene-1-carboxamide (0.48 g),
N-[(1-ethylpyrazol-4-yl)methyl]-7-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-t-
etrahydronaphthalene-1-carboxamide (0.34 g) was obtained. melting point:
169-170° C.

Example 76

##STR00095##

[0602]By the reaction and treatment in the same manner as in Example 37
using 4-benzyloxy-N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)in-
dan-1-carboxamide (0.70 g),
N-[(1-ethylpyrazol-4-yl)methyl]-4-hydroxy-N-(4-isopropylphenyl)indan-1-ca-
rboxamide (0.51 g) was obtained. melting point: 205-206° C.

Example 77

##STR00096##

[0604]By the reaction and treatment in the same manner as in Example 37
using 6-benzyloxy-N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-1-
,2,3,4-tetrahydronaphthalene-1-carboxamide (0.56 g),
N-[(1-ethylpyrazol-4-yl)methyl]-6-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-t-
etrahydronaphthalene-1-carboxamide (0.42 g) was obtained. melting point:
146-147° C.

Example 78

##STR00097##

[0606]By the reaction and treatment in the same manner as in Example 4
using 5-methoxyindan-1-carboxylic acid (0.29 g) and
[(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.37 g) as
starting materials,
N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-5-methoxyindan-1-ca-
rboxamide (0.47 g) was obtained. melting point: 115-116° C.

Example 79

##STR00098##

[0608]By the reaction and treatment in the same manner as in Example 12
using 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.26 g) and
[(1-benzylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.46 g) as
starting materials,
N-[(1-benzylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydro-
naphthalene-1-carboxamide (0.55 g) was obtained.

[0611]By the reaction and treatment in the same manner as in Example 12
using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.56
g) and [(1-benzylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.61 g) as
starting materials,
5-benzyloxy-N-[(1-benzylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,-
4-tetrahydronaphthalene-1-carboxamide (0.67 g) was obtained.

[0613]By the reaction and treatment in the same manner as in Example 37
using 5-benzyloxy-N-[(1-benzylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)--
1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.66 g),
N-[(1-benzylpyrazol-4-yl)methyl]-5-hydroxy-N-(4-isopropylphenyl)-1,2,3,4--
tetrahydronaphthalene-1-carboxamide (0.47 g) was obtained. melting point:
130.1° C.

Example 81

##STR00100##

[0615]By the reaction and treatment in the same manner as in Example 12
using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.39
g) and (4-isopropylphenyl)[(6-methoxypyridin-3-yl)methyl]amine (0.35 g)
as starting materials,
5-benzyloxy-N-(4-isopropylphenyl)-N-[(6-methoxypyridin-3-yl)methyl]-1,2,3-
,4-tetrahydronaphthalene-1-carboxamide (0.36 g) was obtained.

[0617]By the reaction and treatment in the same manner as in Example 37
using 5-benzyloxy-N-(4-isopropylphenyl)-N-[(6-methoxypyridin-3-yl)methyl]-
-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.36 g),
5-hydroxy-N-(4-isopropylphenyl)-N-[(6-methoxypyridin-3-yl)methyl]-1,2,3,4-
-tetrahydronaphthalene-1-carboxamide (0.25 g) was obtained. melting point:
157.9° C.

Example 82

##STR00101##

[0619]1-(tert-Butyloxycarbonyl)-4-(hydroxymethyl)pyrazole-(3.98 g) was
dissolved in methylene chloride (50 mL), and methanesulfonyl chloride
(1.63 mL) was added under ice-cooling. The mixture was stirred at room
temperature for one day. The reaction mixture was concentrated and
partitioned between water and chloroform. The organic layer was washed
with saturated brine and dried over anhydrous sodium sulfate. The solvent
was evaporated to give a residue (4.20 g). A white amorphous solid (5.20
g) obtained by the reaction and treatment in the same manner as in
Example 6 using the residue and
N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxami-
de (5.96 g) was dissolved in 4 mol/L-HCl/dioxane (50 mL). The mixture was
stirred at room temperature for 3 hr, and the reaction mixture was
concentrated under reduced pressure. Ethyl acetate and hexane were added
to the residue. The precipitated solid was collected by filtration to
give N-(4-isopropylphenyl)-7-methoxy-N-[(pyrazol-4-yl)methyl]-N-1,2,3,4-t-
etrahydronaphthalene-1-carboxamide hydrochloride (4.17 g).

[0622]N-(4-Isopropylphenyl)-7-methoxy-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tet-
rahydronaphthalene-1-carboxamide (0.44 g) and cyclopentyl bromide (0.12
mL) were dissolved in DMF (5 mL), and sodium hydride (0.09 g) was added
under ice-cooling. The mixture was stirred at the same temperature for 30
min and then at room temperature for 5 hr. The reaction mixture was
concentrated under reduced pressure and partitioned between water and
ethyl acetate. The organic layer was washed with saturated brine and
dried over anhydrous sodium sulfate. The solvent was evaporated, and the
residue was purified by silica gel column chromatography to give
N-[(1-cyclopentylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2-
,3,4-tetrahydronaphthalene-1-carboxamide (0.38 g).

[0625]By the reaction and treatment in the same manner as in Example 83
using N-(4-isopropylphenyl)-7-methoxy-N-[(pyrazol-4-yl)methyl]-1,2,3,4-te-
trahydronaphthalene-1-carboxamide (0.44 g) and isopropyl iodide (0.11 mL)
as starting materials,
N-(4-isopropylphenyl)-N-[(1-isopropylpyrazol-4-yl)methyl]-7-methoxy-1,2,3-
,4-tetrahydronaphthalene-1-carboxamide (0.26 g) was obtained.

[0628]By the reaction and treatment in the same manner as in Example 83
using N-(4-isopropylphenyl)-7-methoxy-N-[(pyrazol-4-yl)methyl]-1,2,3,4-te-
trahydronaphthalene-1-carboxamide (0.44 g) and ethyl iodide (0.09 mL) as
starting materials,
N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-t-
etrahydronaphthalene-1-carboxamide (0.31 g) was obtained. This was
dissolved in ethyl acetate, and oxalic acid (0.07 g) was added. The
precipitated solid was collected by filtration to give
N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-t-
etrahydronaphthalene-1-carboxamide oxalate (0.06 g).

[0631]By the reaction and treatment in the same manner as in Example 83
using N-(4-isopropylphenyl)-7-methoxy-N-[(pyrazol-4-yl)methyl]-1,2,3,4-te-
trahydronaphthalene-1-carboxamide (0.44 g) and propyl iodide (0.01 mL) as
starting materials,
N-(4-isopropylphenyl)-N-[(1-propylpyrazol-4-yl)methyl]-7-methoxy-1,2,3,4--
tetrahydronaphthalene-1-carboxamide (0.31 g) was obtained.

[0634]By the reaction and treatment in the same manner as in Example 82
using 1-(tert-butyloxycarbonyl)-4-(hydroxymethyl)pyrazole (578 mg) and
5-benzyloxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-c-
arboxamide (1.17 g) as starting materials,
5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4--
tetrahydronaphthalene-1-carboxamide hydrochloride (790 mg) was obtained.
melting point: 184.7° C.

Example 88

##STR00107##

[0636]By the reaction and treatment in the same manner as in Example 83
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,-
2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.79 g) and ethyl
iodide (0.12 mL) as starting materials,
5-benzyloxy-N-[(1-ethylpyrazol-4-yl)methyl]-N-(6-isopropylpyridin-3-yl)-1-
,2,3,4-tetrahydronaphthalene-1-carboxamide (0.43 g) was obtained.

[0639]By the reaction and treatment in the same manner as in Example 37
using 5-benzyloxy-N-[(1-ethylpyrazol-4-yl)methyl]-N-(6-isopropylpyridin-3-
-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.43 g),
N-[(1-ethylpyrazol-4-yl)methyl]-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2-
,3,4-tetrahydronaphthalene-1-carboxamide (0.33 g) was obtained. melting
point: 172.8° C.

[0660]By the reaction and treatment in the same manner as in Example 12
using 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.63 g)
and (4-acetylphenyl)[(4-methoxyphenyl)methyl]amine (0.78 g) as starting
materials,
N-(4-acetylphenyl)-7-methoxy-N-[(4-methoxyphenyl)methyl]-1,2,3,4-tetrahyd-
ronaphthalene-1-carboxamide (0.33 g) was obtained.

[0663]By the reaction and treatment in the same manner as in Example 12
using 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.41 g)
and {[4-(diethoxymethyl)phenyl]-methyl}(4-isopropylphenyl)amine (0.65 g)
as starting materials. The obtained residue was dissolved in a mixed
solvent (15 mL) of methanol:1 mol/L-hydrochloric acid (1:2) and heated
under reflux for 3 hr. The reaction mixture was concentrated under
reduced pressure and partitioned between water and ethyl acetate. The
organic layer was washed with saturated brine and dried over anhydrous
magnesium sulfate. The solvent was evaporated and the residue was
purified by silica gel column chromatography to give
N-[(4-formylphenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrah-
ydronaphthalene-1-carboxamide (0.42 g).

[0666]N-[(4-Formylphenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-t-
etrahydronaphthalene-1-carboxamide (0.42 g) was dissolved in a mixed
solvent (10 mL) of ethanol: tetrahydrofuran (2:1), and sodium borohydride
(0.15 g) was added under ice-cooling. The mixture was stirred at room
temperature for 3 hr. The reaction mixture was partitioned between water
and ethyl acetate. The organic layer was washed with saturated brine and
dried over sodium sulfate. The solvent was evaporated, and the residue
was purified by silica gel column chromatography to give
N-{[4-(hydroxymethyl)phenyl]methyl}-N-(4-isopropylphenyl)-7-methoxy-1,2,3-
,4-tetrahydronaphthalene-1-carboxamide (0.25 g). melting point:
143.2° C.

[0669]By the reaction and treatment in the same manner as in Example 12
using 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.62 g)
and [(4-bromophenyl)methyl](4-octylphenyl)amine (1.12 g) as starting
materials,
N-[(4-bromophenyl)methyl]-7-methoxy-N-(4-octylphenyl)-1,2,3,4-tetrahydron-
aphthalene-1-carboxamide (1.15 g) was obtained.

[0672]By the reaction and treatment in the same manner as in Example 12
using 8-(benzyloxy)chroman-4-carboxylic acid (0.47 g) and
(4-isopropylphenyl)[(6-methoxypyridin-3-yl)methyl]amine 0.43 g) as
starting materials,
8-benzyloxy-N-(4-isopropylphenyl)-N-[(6-methoxypyridin-3-yl)methyl]chroma-
n-4-carboxamide (0.61 g) was obtained.

[0675]By the reaction and treatment in the same manner as in Example 17
using 8-benzyloxy-N-(4-isopropylphenyl)-N-[(6-methoxypyridin-3-yl)methyl]-
chroman-4-carboxamide (0.58 g) as a starting material,
8-hydroxy-N-(4-isopropylphenyl)-N-[(6-methoxypyridin-3-yl)methyl]chroman--
4-carboxamide (0.35 g) was obtained.

[0676]melting point: 141.2° C.

Example 99

##STR00118##

[0678]By the reaction and treatment in the same manner as in Example 12
using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.42
g) and [(2,6-dimethoxypyridin-3-yl)methyl](4-isopropylphenyl)amine (0.43
g) as starting materials,
5-benzyloxy-N-[(2,6-dimethoxypyridin-3-yl)methyl]-N-(4-isopropylphenyl)-1-
,2,3,4-tetrahydronaphthalene-1-carboxamide (0.71 g) was obtained.

[0679]By the reaction and treatment in the same manner as in Example 17
using this compound (0.70 g),
N-[(2,6-dimethoxypyridin-3-yl)methyl]-5-hydroxy-N-(4-isopropylphenyl)-1,2-
,3,4-tetrahydronaphthalene-1-carboxamide (0.41 g) was obtained. melting
point: 190.5° C.

Example 100

##STR00119##

[0681]By the reaction and treatment in the same manner as in Example 12
using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.42
g) and (4-isopropylphenyl)[(6-phenoxypyridin-3-yl)methyl]amine (0.47 g)
as starting materials,
5-benzyloxy-N-(4-isopropylphenyl)-N-[(6-phenoxypyridin-3-yl)methyl]-1,2,3-
,4-tetrahydronaphthalene-1-carboxamide (0.42 g) was obtained.

[0684]To a solution of
5-benzyloxy-N-(4-isopropylphenyl)-N-[(6-phenoxypyridin-3-yl)methyl]-1,2,3-
,4-tetrahydronaphthalene-1-carboxamide (0.42 g) in methanol (3 mL) were
added 10% palladium carbon (0.05 g) and ammonium formate (0.23 g), and
the mixture was stirred at room temperature for one day. The reaction
mixture was filtrated, and the solvent was evaporated. The residue was
purified by silica gel column chromatography to give
5-hydroxy-N-(4-isopropylphenyl)-N-[(6-phenoxypyridin-3-yl)methyl]-1,2,3,4-
-tetrahydronaphthalene-1-carboxamide. This compound was dissolved in ethyl
acetate, and 4 mol/L-hydrochloric acid/dioxane (0.20 mL) was added. The
precipitated solid was collected by filtration to give
5-hydroxy-N-(4-isopropylphenyl)-N-[(6-phenoxypyridin-3-yl)methyl]-1,2,3,4-
-tetrahydronaphthalene-1-carboxamide hydrochloride (0.11 g).

[0687]By the reaction and treatment in the same manner as in Example 12
using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.56
g) and [(6-dimethylaminopyridin-3-yl)methyl](4-isopropylphenyl)amine
(0.54 g) as starting materials,
5-benzyloxy-N-[(6-dimethylaminopyridin-3-yl)methyl]-N-(4-isopropylphenyl)-
-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.83 g) was obtained.

[0690]By the reaction and treatment in the same manner as in Example 17
using 5-benzyloxy-N-[(6-dimethylaminopyridin-3-yl)methyl]-N-(4-isopropylp-
henyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.83 g) as a starting
material, N-[(6-dimethylaminopyridin-3-yl)methyl]-5-hydroxy-N-(4-isopropy-
lphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.33 g) was
obtained. melting point: 186.6° C.

Example 104

##STR00123##

[0692]By the reaction and treatment in the same manner as in Example 12
using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.85
g) and (4-isopropylphenyl)[(1-phenylpyrazol-4-yl)methyl]amine (0.87 g) as
starting materials,
5-benzyloxy-N-(4-isopropylphenyl)-N-[(1-phenylpyrazol-4-yl)methyl]-1,2,3,-
4-tetrahydronaphthalene-1-carboxamide (1.21 g) was obtained.

[0695]To a solution of
5-benzyloxy-N-(4-isopropylphenyl)-N-[(1-phenylpyrazol-4-yl)methyl]-1,2,3,-
4-tetrahydronaphthalene-1-carboxamide (1.04 g) in methanol (10 mL) were
added 10% palladium carbon (0.10 g) and ammonium formate (0.59 g), and
the mixture was stirred at room temperature for one day. The reaction
mixture was filtrated, and the solvent was evaporated. The residue was
purified by silica gel column chromatography to give
5-hydroxy-N-(4-isopropylphenyl)-N-[(1-phenylpyrazol-4-yl)methyl]-1,2,3,4--
tetrahydronaphthalene-1-carboxamide (0.76 g).

[0698]To a solution of
N-[(4-dimethylaminophenyl)methyl]-6-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-
-tetrahydronaphthalene-1-carboxamide (0.66 g) in dimethylformamide (10 mL)
were added 2-chloro-N,N-dimethylethylamine hydrochloride (0.26 g) and
potassium carbonate (0.62 g), and the mixture was stirred with heating at
50° C. for 3 hr. The reaction mixture was partitioned between
water and ethyl acetate. The organic layer was washed with saturated
brine and dried over magnesium sulfate. The solvent was evaporated, and
the residue was purified by silica gel column chromatography to give
6-[2-(dimethylamino)ethoxy]-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopro-
pylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide 1/5 hydrate (0.1
g). melting point: 132.6° C.

[0699]MS (ESI) m/z: 514 [MH].sup.+

Example 107

##STR00126##

[0701]By the reaction and treatment in the same manner as in Example 106
using N-[(4-dimethylaminophenyl)methyl]-6-hydroxy-N-(4-isopropylphenyl)-1-
,2,3,4-tetrahydronaphthalene-1-carboxamide (0.66 g) and 2-bromoethanol
(0.16 mL) as starting materials,
N-[(4-dimethylaminophenyl)methyl]-6-(2-hydroxyethoxy)-N-(4-isopropylpheny-
l)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.28 g) was obtained.
melting point: 141.4° C.

Example 108

##STR00127##

[0703]By the reaction and treatment in the same manner as in Example 106
using N-[(4-dimethylaminophenyl)methyl]-5-hydroxy-N-(4-isopropylphenyl)-1-
,2,3,4-tetrahydronaphthalene-1-carboxamide (0.66 g) and 2-bromoethanol
(0.32 mL) as starting materials,
N-[(4-dimethylaminophenyl)methyl]-5-(2-hydroxyethoxy)-N-(4-isopropylpheny-
l)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.49 g) was obtained.

[0706]By the reaction and treatment in the same manner as in Example 106
using N-[(4-dimethylaminophenyl)methyl]-7-hydroxy-N-(4-isopropylphenyl)-1-
,2,3,4-tetrahydronaphthalene-1-carboxamide (0.5 g) and ethyl iodide (0.14
mL) as starting materials,
7-ethoxy-N-{[4-(ethylmethylamino)phenyl]methyl}-N-(4-isopropylphenyl)-1,2-
,3,4-tetrahydronaphthalene-1-carboxamide (0.1 g) was obtained.

[0709]N-[(4-Dimethylaminophenyl)methyl]-7-hydroxy-N-(4-isopropylphenyl)-1,-
2,3,4-tetrahydronaphthalene-1-carboxamide (0.5 g) and ethyl iodide (0.14
mL) were dissolved in dimethylformamide (5 mL), and sodium hydride (0.07
g) was added under ice-cooling. The mixture was stirred at room
temperature for 24 hr. The reaction mixture was partitioned between water
and ethyl acetate. The organic layer was washed with saturated brine and
dried over magnesium sulfate. The solvent was evaporated, and the residue
was purified by silica gel column chromatography to give
N-[(4-dimethylaminophenyl)methyl]-7-ethoxy-N-(4-isopropylphenyl)-1,2,3,4--
tetrahydronaphthalene-1-carboxamide (0.27 g).

[0712]By the reaction and treatment in the same manner as in Example 110
using N-[(4-dimethylaminophenyl)methyl]-7-hydroxy-N-(4-isopropylphenyl)-1-
,2,3,4-tetrahydronaphthalene-1-carboxamide (0.5 g) and butyl bromide (0.18
mL) as starting materials,
7-butoxy-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-1,2,3,4--
tetrahydronaphthalene-1-carboxamide (0.15 g) was obtained.

[0715]By the reaction and treatment in the same manner as in Example 106
using N-[(4-dimethylaminophenyl)methyl]-7-hydroxy-N-(4-isopropylphenyl)-1-
,2,3,4-tetrahydronaphthalene-1-carboxamide (0.5 g) and 2-iodopropane (0.17
mL) as starting materials,
N-[(4-dimethylaminophenyl)methyl]-7-isopropoxy-N-(4-isopropylphenyl)-1,2,-
3,4-tetrahydronaphthalene-1-carboxamide (35 mg) was obtained.

[0718]By the reaction and treatment in the same manner as in Example 106
using N-[(4-dimethylaminophenyl)methyl]-5-hydroxy-N-(4-isopropylphenyl)-1-
,2,3,4-tetrahydronaphthalene-1-carboxamide (0.66 g) and
2-chloro-N,N-dimethylethylamine hydrochloride (0.32 g) as starting
materials,
5-[2-(dimethylamino)ethoxy]-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopro-
pylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.54 g) was
obtained. This compound was dissolved in ethyl acetate, and oxalic acid
was added. The precipitated solid was subjected to recrystallization from
ethyl acetate to give
5-[2-(dimethylamino)ethoxy]-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopro-
pylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide oxalate 1/4 hydrate
(93.8 mg).

[0719]melting point: 155.7° C.

Example 114

##STR00133##

[0721]By the reaction and treatment in the same manner as in Example 110
using N-[(4-dimethylaminophenyl)methyl]-7-hydroxy-N-(4-isopropylphenyl)-1-
,2,3,4-tetrahydronaphthalene-1-carboxamide (0.5 g),
2-chloro-N,N-dimethylethylamine hydrochloride (0.36 g) and sodium iodide
(0.51 g) as starting materials,
7-[2-(dimethylamino)ethoxy]-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopro-
pylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (36 mg) was
obtained.

[0724]By the reaction and treatment in the same manner as in Example 106
using N-[(4-dimethylaminophenyl)methyl]-5-hydroxy-N-(4-isopropylphenyl)-1-
,2,3,4-tetrahydronaphthalene-1-carboxamide (0.66 g) and
(5,6-dihydroimidazo[2,1-b]thiazol-3-yl)methyl chloride (0.38 g) as
starting materials,
5-[(5,6-dihydroimidazo[2,1-b]thiazol-3-yl)methoxy]-N-[(4-dimethylaminophe-
nyl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxam-
ide (0.16 g) was obtained.

[0727]By the reaction and treatment in the same manner as in Example 106
using N-[(4-dimethylaminophenyl)methyl]-5-hydroxy-N-(4-isopropylphenyl)-1-
,2,3,4-tetrahydronaphthalene-1-carboxamide (0.66 g) and
3-chloro-N,N-dimethylpropylamine hydrochloride (0.32 g) as starting
materials,
N-[(4-dimethylaminophenyl)-methyl]-5-[3-(dimethylamino)propoxy]-N-(4-isop-
ropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.5 g) was
obtained. Oxalic acid was added to this compound. By recrystallization
from isopropyl alcohol,
N-[(4-dimethylaminophenyl)methyl]-5-[3-(dimethylamino)propoxy]-N-(4-isopr-
opylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide oxalate 4/5
hydrate (0.18 g) was obtained.

[0728]melting point: 100.8° C.

Example 117

##STR00136##

[0730]By the reaction and treatment in the same manner as in Example 12
using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (2.3 g)
and methyl 4-{[(4-isopropylphenyl)amino]methyl}benzoate (2.3 g) as
starting materials, methyl
4-{[N-(5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-ylcarbonyl)-N-(4-isopro-
pylphenyl)amino]methyl}benzoate (2.56 g) was obtained.

[0733]Methanol (14 mL) and 1 mol/L-aqueous sodium hydroxide solution (7
mL) were added to methyl
4-{[N-(5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-ylcarbonyl)-N-(4-isopro-
pylphenyl)amino]methyl}benzoate (2.56 g), and the mixture was stirred with
heating at 50-60° C. After the completion of the reaction, the
reaction mixture was neutralized with conc. hydrochloric acid and
extracted with ethyl acetate. The organic layer was washed with saturated
brine and dried over magnesium sulfate. The solvent was evaporated, and
the residue was purified by silica gel column chromatography to give
4-{[N-(5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-ylcarbonyl)-N-(4-isopro-
pylphenyl)amino]methyl}benzoic acid (2 g).

[0736]By the reaction and treatment in the same manner as in Example 17
using 4-{[N-(5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-ylcarbonyl)-N-(4--
isopropylphenyl)amino]methyl}benzoic acid (2 g) as a starting material,
4-{[N-(5-hydroxy-1,2,3,4-tetrahydronaphthalen-1-ylcarbonyl)-N-(4-isopropy-
lphenyl)amino]methyl}benzoic acid dihydrate (0.13 g) was obtained. melting
point: 231.4° C.

Example 120

##STR00139##

[0738]By the reaction and treatment in the same manner as in Example 12
using 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.7 g) and
[(5-ethylthiophen-2-yl)methyl](4-isopropylphenyl)amine (1.04 g) as
starting materials, N-[(5-ethylthiophen-2-yl)
methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide
(0.18 g) was obtained.

[0742]By the reaction and treatment in the same manner as in Example 12
using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.13
g) and [(5-ethylthiophen-2-yl)methyl](4-isopropylphenyl)amine (1.04 g) as
starting materials,
5-benzyloxy-N-[(5-ethylthiophen-2-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,-
4-tetrahydronaphthalene-1-carboxamide (1.01 g) was obtained.

[0745]By the reaction and treatment in the same manner as in Example 12
using 8-benzyloxychroman-4-carboxylic acid (0.54 g) and
[(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.51 g) as
starting materials,
8-benzyloxy-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)chroma-
n-4-carboxamide (1 g) was obtained.

[0746]MS (ESI) m/z: 535 [MH].sup.+

[0747]By the reaction and treatment in the same manner as in Example 17
using this compound,
N-[(4-dimethylaminophenyl)methyl]-8-hydroxy-N-(4-isopropylphenyl)chroman--
4-carboxamide (0.7 g) was obtained.

[0750]By the reaction and treatment in the same manner as in Example 12
using 7-benzyloxychroman-4-carboxylic acid (0.6 g) and
[(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.57 g) as
starting materials,
7-benzyloxy-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)chroma-
n-4-carboxamide (1.2 g) was obtained.

[0753]By the reaction and treatment in the same manner as in Example 17
using 7-benzyloxy-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-
chroman-4-carboxamide (1.0 g) as a starting material,
N-[(4-dimethylaminophenyl)methyl]-7-hydroxy-N-(4-isopropylphenyl)chroman--
4-carboxamide (0.54 g) was obtained. melting point: 173.1° C.

[0759]8-Cyano-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)chrom-
an-4-carboxamide (0.9 g) was dissolved in acetone (12.8 mL), and 1
mol/L-aqueous sodium hydroxide solution (6.4 mL) and 30% aqueous hydrogen
peroxide (3.8 mL) were added. The mixture was heated under reflux for 2
hr. The reaction mixture was partitioned between water and ethyl acetate.
The organic layer was washed with saturated brine and dried over
magnesium sulfate. The solvent was evaporated, and the residue was
purified by silica gel column chromatography to give
8-carbamoyl-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)chroma-
n-4-carboxamide (21 mg).

[0763]By the reaction and treatment in the same manner as in Example 12
using 7-fluoro-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.41 g)
and [(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.57 g) as
starting materials,
N-[(4-dimethylaminophenyl)methyl]-7-fluoro-N-(4-isopropylphenyl)-1,2,3,4--
tetrahydronaphthalene-1-carboxamide (0.85 g) was obtained. This compound
was dissolved in ethyl acetate, and 4 mol/L-HCl/dioxane was added. The
precipitated solid was collected by filtration to give
N-[(4-dimethylaminophenyl)methyl]-7-fluoro-N-(4-isopropylphenyl)-1,2,3,4--
tetrahydronaphthalene-1-carboxamide hydrochloride (0.85 g). melting point:
165.6° C.

[0766]By the reaction and treatment in the same manner as in Example 12
using 7-fluoro-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.41 g)
and [(4-dimethylaminophenyl)methyl](4-methoxyphenyl)amine (0.54 g) as
starting materials,
N-[(4-dimethylaminophenyl)methyl]-7-fluoro-N-(4-methoxyphenyl)-1,2,3,4-te-
trahydronaphthalene-1-carboxamide was obtained. This compound was
dissolved in ethyl acetate, and 4 mol/L-HCl/dioxane was added. The
precipitated solid was collected by filtration to give
N-[(4-dimethylaminophenyl)methyl]-7-fluoro-N-(4-methoxyphenyl)-1,2,3,4-te-
trahydronaphthalene-1-carboxamide hydrochloride 1/2 hydrate (0.52 g).
melting point: 125.4° C.

Example 129

##STR00148##

[0768]By the reaction and treatment in the same manner as in Example 12
using 7-fluoro-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.41 g)
and (4-bromophenyl)[(4-dimethylaminophenyl)methyl]amine (0.64 g) as
starting materials,
N-(4-bromophenyl)-N-[(4-dimethylaminophenyl)methyl]-7-fluoro-1,2,3,4-tetr-
ahydronaphthalene-1-carboxamide (0.26 g) was obtained.

[0771]By the reaction and treatment in the same manner as in Example 12
using 5-benzyloxy-8-fluoro-1,2,3,4-tetrahydronaphthalene-1-carboxylic
acid (0.5 g) and [(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine
(0.45 g) as starting materials,
5-benzyloxy-N-[(4-dimethylaminophenyl)methyl]-8-fluoro-N-(4-isopropylphen-
yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.73 g) was obtained.

[0774]By the reaction and treatment in the same manner as in Example 17
using 5-benzyloxy-N-[(4-dimethylaminophenyl)methyl]-8-fluoro-N-(4-isoprop-
ylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.73 g) as a
starting material,
N-[(4-dimethylaminophenyl)methyl]-8-fluoro-5-hydroxy-N-(4-isopropylphenyl-
)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.19 g) was obtained.

[0778]5-Benzyloxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalen-
e-1-carboxamide (2.03 g) was dissolved in dimethylformamide (27 mL), and
sodium hydride (0.20 g) was added under ice-cooling. The mixture was
stirred at the same temperature for 30 min. A solution of
3-chloromethyl-2,6-dimethoxypyridine (0.95 g) in dimethylformamide (6 mL)
was added dropwise to the reaction mixture, and the mixture was stirred
at room temperature for 3 hr. The reaction mixture was partitioned
between water and ethyl acetate. The organic layer was washed with
saturated brine and dried over anhydrous magnesium sulfate. The solvent
was evaporated, and the residue was purified by silica gel column
chromatography to give
5-benzyloxy-N-[(2,6-dimethoxypyridin-3-yl)methyl]-N-(6-isopropylpyridin-3-
-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.43 g).

[0781]To a solution of
5-benzyloxy-N-[(2,6-dimethoxypyridin-3-yl)methyl]-N-(6-isopropylpyridin-3-
-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.83 g) in
trifluoroacetic acid (2.4 mL) was added thioanisole (0.49 mL), and the
mixture was stirred at room temperature for one day. The reaction mixture
was poured into saturated aqueous sodium hydrogencarbonate and
partitioned with ethyl acetate. The organic layer was washed with
saturated brine and dried over anhydrous magnesium sulfate. The solvent
was evaporated, and the residue was purified by silica gel column
chromatography to give
N-[(2,6-dimethoxypyridin-3-yl)methyl]-5-hydroxy-N-(6-isopropylpyridin-3-y-
l)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.36 g).

[0785]By the reaction and treatment in the same manner as in Example 12
using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.5 g)
and [(4-dimethylaminophenyl)methyl](6-isopropylpyridin-3-yl)amine (0.48
g) as starting materials,
5-benzyloxy-N-[(4-dimethylaminophenyl)methyl]-N-(6-isopropylpyridin-3-yl)-
-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.39 g) was obtained.

[0788]By the reaction and treatment in the same manner as in Example 17
using 5-benzyloxy-N-[(4-dimethylaminophenyl)methyl]-N-(6-isopropylpyridin-
-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.39 g) as a starting
material, N-[(4-dimethylaminophenyl)methyl]-5-hydroxy-N-(6-isopropylpyrid-
in-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (60 mg) was obtained.

[0792]By the reaction and treatment in the same manner as in Example 12
using 5-benzyloxy-8-methyl-1,2,3,4-tetrahydronaphthalene-1-carboxylic
acid (0.5 g) and [(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine
(0.45 g) as starting materials,
5-benzyloxy-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-8-met-
hyl-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.6 g) was obtained.

[0795]By the reaction and treatment in the same manner as in Example 133
using 5-benzyloxy-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-
-8-methyl-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.5 g) as a
starting material,
N-[(4-dimethylaminophenyl)methyl]-5-hydroxy-N-(4-isopropylphenyl)-8-methy-
l-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.34 g) was obtained.
melting point: 189.5° C.

[0798]By the reaction and treatment in the same manner as in Example 132
using 5-chloromethyl-2-methoxypyridine (0.63 g) and
5-benzyloxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-c-
arboxamide (0.87 g) as starting materials,
5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(6-methoxypyridin-3-yl)methyl]-
-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.23 g) was obtained.

[0801]To a solution of
5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(6-methoxypyridin-3-yl)methyl]-
-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.23 g) in trifluoroacetic
acid (7 mL) was added thioanisole (1.40 mL), and the mixture was stirred
at room temperature for one day. The reaction mixture was partitioned
between saturated aqueous sodium hydrogencarbonate and ethyl acetate. The
organic layer was washed with saturated brine and dried over anhydrous
magnesium sulfate. The solvent was evaporated, and the residue was
dissolved in ethyl acetate. Thereto was added 4 mol/L-HCl/dioxane (0.63
mL), and the precipitated solid was collected by filtration to give
5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-[(6-methoxypyridin-3-yl)methyl]-1-
,2,3,4-tetrahydronaphthalene-1-carboxamide dihydrochloride (0.43 g).

[0805]By the reaction and treatment in the same manner as in Example 12
using 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.39 g)
and (4-isopropylphenyl) [(4-pyrrolidinophenyl)methyl]amine (0.56 g) as
starting materials,
N-(4-isopropylphenyl)-7-methoxy-N-[(4-pyrrolidinophenyl)methyl]-1,2,3,4-t-
etrahydronaphthalene-1-carboxamide (0.3 g) was obtained.

[0808]By the reaction and treatment in the same manner as in Example 12
using 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.39 g)
and {[4-(imidazol-1-yl)phenyl]methyl}(4-isopropylphenyl)amine (0.55 g) as
starting materials,
N-{[4-(imidazol-1-yl)phenyl]methyl}-N-(4-isopropylphenyl)-7-methoxy-1,2,3-
,4-tetrahydronaphthalene-1-carboxamide 1/2 hydrate (0.28 g) was obtained.

[0812]2,4-Dimethyl-5-(hydroxymethyl)thiazole (0.65 g) was dissolved in
methylene chloride (15 mL), and methanesulfonyl chloride (0.37 mL) was
added under ice-cooling. The mixture was stirred at room temperature for
one day. The reaction mixture was concentrated, and the residue was
partitioned between water and chloroform. The organic layer was washed
with saturated brine and dried over anhydrous sodium sulfate. The solvent
was evaporated. By the reaction and treatment of the obtained residue and
5-benzyloxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-c-
arboxamide (1.8 g) in the same manner as in Example 132,
5-benzyloxy-N-[(2,4-dimethylthiazol-5-yl)methyl]-N-(6-isopropylpyridin-3--
yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.64 g) was obtained.

[0815]By the reaction and treatment in the same manner as in Example 139
using 5-benzyloxy-N-[(2,4-dimethylthiazol-5-yl)methyl]-N-(6-isopropylpyri-
din-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.64 g) as a
starting material,
N-[(2,4-dimethylthiazol-5-yl)methyl]-5-hydroxy-N-(6-isopropylpyridin-3-yl-
)-1,2,3,4-tetrahydronaphthalene-1-carboxamide dihydrochloride 5/2 hydrate
(0.72 g) was obtained.

[0819]By the reaction and treatment in the same manner as in Example 142
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthale-
ne-1-carboxamide (1.2 g) and 3-hydroxymethyl-6-(2-methoxyethoxy)pyridine
(0.55 g) as starting materials,
5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-{[6-(2-methoxyethoxy)pyridin-3--
yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.07 g) was
obtained.

[0822]By the reaction and treatment in the same manner as in Example 133
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-{[6-(2-methoxyethoxy)pyri-
din-3-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.07 g) as a
starting material,
5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-{[6-(2-methoxyethoxy)pyridin-3-yl-
]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.72 g) was
obtained.

[0828]By the reaction and treatment in the same manner as in Example 12
using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.54
g) and {[4-(imidazol-1-yl)phenyl]methyl}(4-isopropylphenyl)amine (0.55 g)
as starting materials,
5-benzyloxy-N-{[4-(imidazol-1-yl)phenyl]methyl-}-N-(4-isopropylphenyl)-1,-
2,3,4-tetrahydronaphthalene-1-carboxamide (0.62 g) was obtained.

[0831]By the reaction and treatment in the same manner as in Example 133
using 5-benzyloxy-N-{[4-(imidazol-1-yl)phenyl]methyl}-N-(4-isopropylpheny-
l)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.62 g) as a starting
material, 5-hydroxy-N-{[4-(imidazol-1-yl)phenyl]methyl}-N-(4-isopropylphe-
nyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.36 g) was obtained.

[0834]By the reaction and treatment in the same manner as in Example 12
using 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.70 g) and
(4-butylphenyl)[(4-dimethylaminophenyl)methyl]amine (0.54 g) as starting
materials,
N-(4-butylphenyl)-N-[(4-dimethylaminophenyl)methyl]-1,2,3,4-tetrahydronap-
hthalene-1-carboxamide (0.81 g) was obtained.

[0837]By the reaction and treatment in the same manner as in Example 12
using 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.34 g) and
(4-ethylphenyl)[(4-morpholinophenyl)methyl]amine (0.59 g) as starting
materials,
N-(4-ethylphenyl)-N-[(4-morpholinophenyl)methyl]-1,2,3,4-tetrahydronaphth-
alene-1-carboxamide (0.60 g) was obtained.

[0840]By the reaction and treatment in the same manner as in Example 12
using 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.34 g) and
(4-ethylphenyl)(2-piperidinoethyl)amine (0.47 g) as starting materials,
N-(4-ethylphenyl)-N-(2-piperidinoethyl)-1,2,3,4-tetrahydronaphthalene-1-c-
arboxamide (0.65 g) was obtained.

[0843]By the reaction and treatment in the same manner as in Example 12
using 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.70 g) and
[(4-dimethylaminophenyl)methyl](6-methoxypyridin-3-yl)amine (0.49 g) as
starting materials,
N-[(4-dimethylaminophenyl)methyl]-N-(6-methoxypyridin-3-yl)-1,2,3,4-tetra-
hydronaphthalene-1-carboxamide (0.54 g) was obtained.

[0846]By the reaction and treatment in the same manner as in Example 12
using 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.34 g) and
[(4-benzyloxyphenyl)methyl](4-isopropylphenyl)amine (0.66 g) as starting
materials,
N-[(4-benzyloxyphenyl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronap-
hthalene-1-carboxamide (0.52 g) was obtained. melting point:
120-121° C.

Example 154

##STR00173##

[0848]By the reaction and treatment in the same manner as in Example 17
using N-[(4-benzyloxyphenyl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahy-
dronaphthalene-1-carboxamide (0.39 g) as a starting material,
N-[(4-hydroxyphenyl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronapht-
halene-1-carboxamide (0.23 g) was obtained. melting point: 156° C.

Example 155

##STR00174##

[0850]By the reaction and treatment in the same manner as in Example 83
using 5-benzyloxy-N-(4-isopropylphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4--
tetrahydronaphthalene-1-carboxamide (0.52 g) and
3-chloro-N,N-dimethylpropylamine hydrochloride (0.49 g) as starting
materials,
5-benzyloxy-N-(4-isopropylphenyl)-N-({1-[3-(dimethylamino)propyl]pyrazol--
4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.1 g) was
obtained. By the reaction and treatment in the same manner as in Example
105 using this compound,
N-({1-[3-(dimethylamino)propyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(4-isopro-
pylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.73 g) was
obtained.

[0853]By the reaction and treatment in the same manner as in Example 12
using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.63
g) and (4-ethylphenyl)[(4-morpholinophenyl)methyl]amine (0.56 g) as
starting materials,
5-benzyloxy-N-(4-ethylphenyl)-N-[(4-morpholinophenyl)methyl]-1,2,3,4-tetr-
ahydronaphthalene-1-carboxamide (0.75 g) was obtained. By the reaction and
treatment in the same manner as in Example 17 using this compound,
N-(4-ethylphenyl)-5-hydroxy-N-[(4-morpholinophenyl)methyl]-1,2,3,4-tetrah-
ydronaphthalene-1-carboxamide (0.51 g) was obtained. melting point:
200° C.

Example 157

##STR00176##

[0855]By the reaction and treatment in the same manner as in Example 12
using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.66
g) and (4-butylphenyl)[(4-dimethylaminophenyl)methyl]amine (0.55 g) as
starting materials,
5-benzyloxy-N-(4-butylphenyl)-N-[(4-dimethylaminophenyl)methyl]-1,2,3,4-t-
etrahydronaphthalene-1-carboxamide (0.98 g) was obtained. By the reaction
and treatment in the same manner as in Example 17 using this compound,
N-(4-butylphenyl)-N-[(4-dimethylaminophenyl)methyl]-5-hydroxy-1,2,3,4-tet-
rahydronaphthalene-1-carboxamide (0.44 g) was obtained. melting point:
138° C.

Example 158

##STR00177##

[0857]By the reaction and treatment in the same manner as in Example 12
using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.72
g) and (4-ethylphenyl) (2-piperidinoethyl)amine (0.50 g) as starting
materials,
5-benzyloxy-N-(4-ethylphenyl)-N-(2-piperidinoethyl)-1,2,3,4-tetrahydronap-
hthalene-1-carboxamide (1.19 g) was obtained. By the reaction and
treatment in the same manner as in Example 105 using this compound,
N-(4-ethylphenyl)-5-hydroxy-N-(2-piperidinoethyl)-1,2,3,4-tetrahydronapht-
halene-1-carboxamide (0.77 g) was obtained.

[0860]By the reaction and treatment in the same manner as in Example 12
using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.94
g) and [(3,4-dibenzyloxyphenyl)methyl](4-isopropylphenyl)amine (2.5 g) as
starting materials,
5-benzyloxy-N-[(3,4-dibenzyloxyphenyl)methyl]-N-(4-isopropylphenyl)-1,2,3-
,4-tetrahydronaphthalene-1-carboxamide (2.64 g) was obtained. By the
reaction and treatment in the same manner as in Example 17 using this
compound, N-[(3,4-dihydroxyphenyl)methyl]-5-hydroxy-N-(4-isopropylphenyl)-
-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.35 g) was obtained.

[0863]By the reaction and treatment in the same manner as in Example 12
using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.59
g) and [(4-benzyloxyphenyl)methyl](4-isopropylphenyl)amine (0.58 g) as
starting materials,
5-benzyloxy-N-[(4-benzyloxyphenyl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-t-
etrahydronaphthalene-1-carboxamide (0.74 g) was obtained. By the reaction
and treatment in the same manner as in Example 17 using this compound,
5-hydroxy-N-[(4-hydroxyphenyl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetra-
hydronaphthalene-1-carboxamide (0.33 g) was obtained. melting point:
241-243° C.

Example 161

##STR00180##

[0865]By the reaction and treatment in the same manner as in Example 12
using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.0 g)
and [(4-dimethylaminophenyl)methyl](6-methoxypyridin-3-yl)amine (0.91 g)
as starting materials,
5-benzyloxy-N-[(4-dimethylaminophenyl)methyl]-N-(6-methoxypyridin-3-yl)-1-
,2,3,4-tetrahydronaphthalene-1-carboxamide (1.35 g) was obtained. By the
reaction and treatment in the same manner as in Example 105 using this
compound, N-[(4-dimethylaminophenyl)methyl]-5-hydroxy-N-(6-methoxypyridin-
-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.34 g) was obtained.

[0868]Aniline (93.1 mg) was dissolved in dichloroethane (5 mL), and
4-dimethylaminobenzaldehyde (149 mg), acetic acid (0.06 mL) and sodium
triacetoxy borohydride (0.42 g) were added. The mixture was stirred at
room temperature for one day. Saturated aqueous sodium hydrogencarbonate
(2 mL) was added to the reaction solution, and the mixture was stirred
for a while, after which the aqueous layer was absorbed using a
diatomaceous earth column. The obtained organic layer was concentrated
under reduced pressure, and dichloromethane (5 mL) was added to the
residue. To this solution was added a solution of
7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid chloride (0.23
g) in dichloromethane (5 mL), and the mixture was stirred at room
temperature for one day. Saturated aqueous sodium hydrogencarbonate (2
mL) was added to the reaction solution. The mixture was stirred for a
while, after which the aqueous layer was absorbed using a diatomaceous
earth column. The obtained organic layer was concentrated under reduced
pressure, and the residue was purified by silica gel column
chromatography to give
N-[(4-dimethylaminophenyl)methyl]-7-methoxy-N-phenyl-1,2,3,4-tetrahydrona-
phthalene-1-carboxamide (260 mg).

[0871]By the reaction and treatment in the same manner as in Example 162
using 4-methoxyaniline (0.12 g) as a starting material instead of
aniline, N-[(4-dimethylaminophenyl)methyl]-7-methoxy-N-(4-methoxyphenyl)--
1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.12 g) was obtained.

[0874]By the reaction and treatment in the same manner as in Example 162
using 4-cyclohexylaniline (0.18 g) as a starting material instead of
aniline, N-(4-cyclohexylphenyl)-N-[(4-dimethylaminophenyl)methyl]-7-metho-
xy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.088 g) was obtained.

[0877]By the reaction and treatment in the same manner as in Example 162
using 3,4-dimethylaniline (0.12 g) as a starting material instead of
aniline, N-[(4-dimethylaminophenyl)methyl]-N-(3,4-dimethylphenyl)-7-metho-
xy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.29 g) was obtained.

[0880]By the reaction and treatment in the same manner as in Example 162
using 3,4-dichloroaniline (0.16 g) as a starting material instead of
aniline, N-(3,4-dichlorophenyl)-N-[(4-dimethylaminophenyl)methyl]-7-metho-
xy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.14 g) was obtained.

[0883]N-(4-Isopropylphenyl)-7-methoxy-N-[(4-nitrophenyl)methyl]-1,2,3,4-te-
trahydronaphthalene-1-carboxamide (1.2 g) was dissolved in ethanol (8.1
mL), and stannic chloride (1.5 g) and conc. hydrochloric acid (2.7 mL)
were added. The mixture was heated under reflux for 3 hr. The reaction
mixture was concentrated under reduced pressure, and the residue was
partitioned between water and ethyl acetate. The organic layer was washed
with saturated aqueous sodium hydrogencarbonate and dried over magnesium
sulfate. The solvent was evaporated under reduced pressure, and the
obtained solid was recrystallized from a mixed solvent of chloroform and
diisopropyl ether to give
N-[(4-aminophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahy-
dronaphthalene-1-carboxamide (1.0 g).

[0884]melting point: 115-117° C.

Example 168

##STR00187##

[0886]By the reaction and treatment in the same manner as in Example 162
using 4-morpholinoaniline (0.18 g) as a starting material instead of
aniline, N-[(4-dimethylaminophenyl)
methyl]-7-methoxy-N-(4-morpholinophenyl)-1,2,3,4-tetrahydronaphthalene-1--
carboxamide (0.33 g) was obtained.

[0889]By the reaction and treatment in the same manner as in Example 162
using 2,6-dimethylaniline (0.12 g) as a starting material instead of
aniline, N-[(4-dimethylaminophenyl)methyl]-N-(2,6-dimethylphenyl)-7-metho-
xy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.16 g) was obtained.

[0892]By the reaction and treatment in the same manner as in Example 162
using 3,4-dimethoxyaniline (0.15 g) as a starting material instead of
aniline, N-(3,4-dimethoxyphenyl)-N-[(4-dimethylaminophenyl)methyl]-7-meth-
oxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.18 g) was obtained.

[0895]By the reaction and treatment in the same manner as in Example 162
using 3,4,5-trimethoxyaniline (0.18 g) as a starting material instead of
aniline, N-[(4-dimethylaminophenyl)methyl]-7-methoxy-N-(3,4,5-trimethoxyp-
henyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.22 g) was obtained.

[0898]By the reaction and treatment in the same manner as in Example 162
using 4-cyanoaniline (0.12 g) as a starting material instead of aniline,
N-(4-cyanophenyl)-N-[(4-dimethylaminophenyl)methyl]-7-methoxy-1,2,3,4-tet-
rahydronaphthalene-1-carboxamide (0.097 g) was obtained.

[0901]By the reaction and treatment in the same manner as in Example 162
using 2-fluoroaniline (0.11 g) as a starting material instead of aniline,
N-[(4-dimethylaminophenyl)methyl]-N-(2-fluorophenyl)-7-methoxy-1,2,3,4-te-
trahydronaphthalene-1-carboxamide (0.41 g) was obtained.

[0904]By the reaction and treatment in the same manner as in Example 162
using 3-fluoroaniline (0.11 g) as a starting material instead of aniline,
N-[(4-dimethylaminophenyl)methyl]-N-(3-fluorophenyl)-7-methoxy-1,2,3,4-te-
trahydronaphthalene-1-carboxamide (0.26 g) was obtained.

[0907]By the reaction and treatment in the same manner as in Example 162
using 4-fluoroaniline (0.11 g) as a starting material instead of aniline,
N-[(4-dimethylaminophenyl)methyl]-N-(4-fluorophenyl)-7-methoxy-1,2,3,4-te-
trahydronaphthalene-1-carboxamide (0.36 g) was obtained.

[0910]By the reaction and treatment in the same manner as in Example 162
using 3-cyanoaniline (0.12 g) as a starting material instead of aniline,
N-(3-cyanophenyl)-N-[(4-dimethylaminophenyl)methyl]-7-methoxy-1,2,3,4-tet-
rahydronaphthalene-1-carboxamide (0.14 g) was obtained.

[0913]By the reaction and treatment in the same manner as in Example 162
using 2-chloroaniline (0.12 g) as a starting material instead of aniline,
N-(2-chlorophenyl)-N-[(4-dimethylaminophenyl)methyl]-7-methoxy-1,2,3,4-te-
trahydronaphthalene-1-carboxamide (0.24 g) was obtained.

[0916]By the reaction and treatment in the same manner as in Example 162
using 3-chloroaniline (0.12 g) as a starting material instead of aniline,
N-(3-chlorophenyl)-N-[(4-dimethylaminophenyl)methyl]-7-methoxy-1,2,3,4-te-
trahydronaphthalene-1-carboxamide (0.23 g) was obtained.

[0919]By the reaction and treatment in the same manner as in Example 162
using 4-chloroaniline (0.12 g) as a starting material instead of aniline,
N-(4-chlorophenyl)-N-[(4-dimethylaminophenyl)methyl]-7-methoxy-1,2,3,4-te-
trahydronaphthalene-1-carboxamide (0.30 g) was obtained.

[0922]By the reaction and treatment in the same manner as in Example 162
using o-toluidine (0.11 g) as a starting material instead of aniline,
N-[(4-dimethylaminophenyl)methyl]-7-methoxy-N-(2-methylphenyl)-1,2,3,4-te-
trahydronaphthalene-1-carboxamide (0.22 g) was obtained.

[0925]By the reaction and treatment in the same manner as in Example 162
using m-toluidine (0.11 g) as a starting material instead of aniline,
N-[(4-dimethylaminophenyl)methyl]-7-methoxy-N-(3-methylphenyl)-1,2,3,4-te-
trahydronaphthalene-1-carboxamide (0.23 g) was obtained.

[0928]By the reaction and treatment in the same manner as in Example 162
using p-toluidine (0.11 g) as a starting material instead of aniline,
N-[(4-dimethylaminophenyl)methyl]-7-methoxy-N-(4-methylphenyl)-1,2,3,4-te-
trahydronaphthalene-1-carboxamide (0.27 g) was obtained.

[0931]By the reaction and treatment in the same manner as in Example 162
using 2-isopropylaniline (0.14 g) as a starting material instead of
aniline, N-[(4-dimethylaminophenyl)methyl]-N-(2-isopropylphenyl)-7-methox-
y-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.12 g) was obtained.

[0934]By the reaction and treatment in the same manner as in Example 162
using 3-isopropylaniline (0.14 g) as a starting material instead of
aniline, N-[(4-dimethylaminophenyl)methyl]-N-(3-isopropylphenyl)-7-methox-
y-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.28 g) was obtained.

[0937]By the reaction and treatment in the same manner as in Example 162
using 2-methoxyaniline (0.12 g) as a starting material instead of
aniline, N-[(4-dimethylaminophenyl)methyl)]-7-methoxy-N-(2-methoxyphenyl)-
-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.29 g) was obtained.

[0940]By the reaction and treatment in the same manner as in Example 162
using 3-methoxyaniline (0.12 g) as a starting material instead of
aniline, N-[(4-dimethylaminophenyl)methyl]-7-methoxy-N-(3-methoxyphenyl)--
1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.20 g) was obtained.

[0943]By the reaction and treatment in the same manner as in Example 162
using 4-ethoxyaniline (0.14 g) as a starting material instead of aniline,
N-[(4-dimethylaminophenyl)methyl]-N-(4-ethoxyphenyl)-7-methoxy-1,2,3,4-te-
trahydronaphthalene-1-carboxamide (0.28 g) was obtained.

[0946]By the reaction and treatment in the same manner as in Example 162
using 4-bromoaniline (0.17 g) as a starting material instead of aniline,
N-(4-bromophenyl)-N-[(4-dimethylaminophenyl)methyl]-7-methoxy-1,2,3,4-tet-
rahydronaphthalene-1-carboxamide (0.25 g) was obtained.

[0949]By the reaction and treatment in the same manner as in Example 162
using 2,4-dichloroaniline (0.16 g) as a starting material instead of
aniline, N-(2,4-dichlorophenyl)-N-[(4-dimethylaminophenyl)methyl]-7-metho-
xy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.12 g) was obtained.

[0952]By the reaction and treatment in the same manner as in Example 162
using 2,4-dimethylaniline (0.12 g) as a starting material instead of
aniline, N-[(4-dimethylaminophenyl)methyl]-N-(2,4-dimethylphenyl)-7-metho-
xy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.29 g) was obtained.

[0955]By the reaction and treatment in the same manner as in Example 162
using 2,4,6-trimethylaniline (0.14 g) as a starting material instead of
aniline, N-[(4-dimethylaminophenyl)methyl]-7-methoxy-N-(2,4,6-trimethylph-
enyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.095 g) was obtained.

[0958]By the reaction and treatment in the same manner as in Example 162
using 2,4-dimethoxyaniline (0.15 g) as a starting material instead of
aniline, N-(2,4-dimethoxyphenyl)-N-[(4-dimethylaminophenyl)methyl]-7-meth-
oxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.39 g) was obtained.

[0961]By the reaction and treatment in the same manner as in Example 162
using 5-amino-1,3-dioxaindane (0.14 g) as a starting material instead of
aniline, N-(1,3-dioxaindan-5-yl)-N-[(4-dimethylaminophenyl)methyl]-7-meth-
oxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.12 g) was obtained.

[0964]By the reaction and treatment in the same manner as in Example 162
using 4-dimethylaminoaniline (0.14 g) as a starting material instead of
aniline, N-(4-dimethylaminophenyl)-N-[(4-dimethylaminophenyl)methyl]-7-me-
thoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.16 g) was obtained.

[0967]N-[(4-Aminophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-te-
trahydronaphthalene-1-carboxamide (6.47 g) was stirred using di-tert-butyl
dicarbonate (in an amount as a solvent) at 80° C. for 2 hr. The
reaction mixture was partitioned between saturated aqueous sodium
hydrogencarbonate and ethyl acetate. The organic layer was washed with
saturated brine and dried over anhydrous magnesium sulfate. The solvent
was evaporated, and the residue was purified by silica gel column
chromatography to give a solid (6.55 g). From the solid, 2.0 g was
dissolved in dimethylformamide (3 mL), and sodium hydride (0.34 g) was
added under cooling. The mixture was stirred at the same temperature for
30 min, and methyl iodide (0.28 mL) was added to the reaction mixture,
which was followed by stirring for 1 hr. The reaction mixture was poured
into iced water and extracted with ethyl acetate. The organic layer was
washed with saturated brine and dried over magnesium sulfate. The solvent
was evaporated under reduced pressure, and the obtained residue was
dissolved in 4 mol/L-HCL/dioxane (5 mL). The mixture was stirred at room
temperature for one day. The reaction mixture was partitioned between
saturated aqueous sodium hydrogencarbonate and ethyl acetate. The organic
layer was washed with saturated brine and dried over magnesium sulfate.
The solvent was evaporated under reduced pressure, and the obtained
residue was purified by silica gel column chromatography to give
N-(4-isopropylphenyl)-7-methoxy-N-[(4-methylaminophenyl)methyl]-1,2,3,4-t-
etrahydronaphthalene-1-carboxamide (1.45 g).

[0970]By the reaction and treatment in the same manner as in Example 162
using N-[(4-aminophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-t-
etrahydronaphthalene-1-carboxamide (0.33 g) and ethyl iodide (0.07 mL) as
starting materials,
N-[(4-ethylaminophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-te-
trahydronaphthalene-1-carboxamide (0.29 g) was obtained.

[0973]By the reaction and treatment in the same manner as in Example 162
using N-[(4-aminophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-t-
etrahydronaphthalene-1-carboxamide (0.33 g) and benzyl bromide (0.1 mL) as
starting materials,
N-[(4-benzylaminophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-t-
etrahydronaphthalene-1-carboxamide (0.13 g) was obtained.

[0974]melting point: 135-138° C.

Example 198

##STR00217##

[0976]By the reaction and treatment in the same manner as in Example 162
using N-[(4-aminophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-t-
etrahydronaphthalene-1-carboxamide (0.41 g) and pentyl bromide (0.14 mL)
as starting materials,
N-(4-isopropylphenyl)-7-methoxy-N-[(4-pentylaminophenyl)methyl]-1,2,3,4-t-
etrahydronaphthalene-1-carboxamide (0.19 g) was obtained.

[0979]N-(4-Isopropylphenyl)-7-methoxy-N-[(4-methylaminophenyl)methyl]-1,2,-
3,4-tetrahydronaphthalene-1-carboxamide (0.77 g) was dissolved in ethanol
(8 mL), and butyl aldehyde (250 mg) and sodium cyanoborohydride (0.22 g)
were added. Acetic acid was added to this solution to pH 5-6, and the
mixture was stirred at room temperature for 2 hr. The reaction mixture
was partitioned between saturated aqueous sodium hydrogencarbonate and
ethyl acetate. The organic layer was washed with saturated brine and
dried over magnesium sulfate. The solvent was evaporated under reduced
pressure and the obtained residue was purified by silica gel column
chromatography to give
N-{[4-(butylmethylamino)phenyl]methyl}-N-(4-isopropylphenyl)-7-methoxy-1,-
2,3,4-tetrahydronaphthalene-1-carboxamide (0.51 g).

[0982]7-Methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.47 g)
and (4-bromophenyl)[(4-dimethylaminophenyl)methyl]-amine (0.70 g) as
starting materials were reacted and treated in the same manner as in
Example 12. The obtained solid was dissolved in ethyl acetate (4 mL).
Thereto was added 4 mol/L-HCl/ethyl acetate (0.35 mL), and the
precipitated solid was collected by filtration to give
N-(4-bromophenyl)-N-[(4-dimethylaminophenyl)methyl]-7-methoxy-1,2,3,4-tet-
rahydronaphthalene-1-carboxamide hydrochloride (0.65 g). melting point:
104-113° C.

Example 201

##STR00220##

[0984]By the reaction and treatment in the same manner as in Example 200
using 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.50 g)
and [(4-dimethylaminophenyl)methyl](4-methoxyphenyl)amine (0.62 g) as
starting materials,
N-[(4-dimethylaminophenyl)methyl]-7-methoxy-N-(4-methoxyphenyl)-1,2,3,4-t-
etrahydronaphthalene-1-carboxamide hydrochloride (0.79 g) was obtained.
melting point: 152° C.

Example 202

##STR00221##

[0986]By the reaction and treatment in the same manner as in Example 12
using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.57
g) and [(4-dimethylaminophenyl)methyl]-4-methoxyphenyl)amine (0.51 g) as
starting materials,
5-benzyloxy-N-[(4-dimethylaminophenyl)methyl]-N-(4-methoxyphenyl)-1,2,3,4-
-tetrahydronaphthalene-1-carboxamide (0.83 g) was obtained. By the
reaction and treatment in the same manner as in Example 17 using this
compound, N-[(4-dimethylaminophenyl)methyl]-5-hydroxy-N-(4-methoxyphenyl)-
-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.33 g) was obtained,
melting point: 195-197° C.

Example 203

##STR00222##

[0988]By the reaction and treatment in the same manner as in Example 12
using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.57
g) and [(4-dimethylaminophenyl)methyl]phenylamine (0.61 g) as starting
materials,
5-benzyloxy-N-[(4-dimethylaminophenyl)methyl]-N-phenyl-1,2,3,4-tetrahydro-
naphthalene-1-carboxamide (0.80 g) was obtained. By the reaction and
treatment in the same manner as in Example 17 using this compound,
N-[(4-dimethylaminophenyl)methyl]-5-hydroxy-N-phenyl-1,2,3,4-tetrahydrona-
phthalene-1-carboxamide (0.083 g) was obtained. melting point:
138-143° C.

Example 204

##STR00223##

[0990]By the reaction and treatment in the same manner as in Example 132
using 5-benzyloxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-c-
arboxamide (0.65 g) and 4-(chloromethyl)-2-methylthiazole (0.30 g) as
starting materials,
5-benzyloxy-N-(4-isopropylphenyl)-N-[(2-methylthiazol-4-yl)methyl]-1,2,3,-
4-tetrahydronaphthalene-1-carboxamide (0.58 g) was obtained. By the
reaction and treatment in the same manner as in Example 133 using this
compound (0.51 g),
5-hydroxy-N-(4-isopropylphenyl)-N-[(2-methylthiazol-4-yl)methyl]-1,2,3,4--
tetrahydronaphthalene-1-carboxamide (0.22 g) was obtained.

[0993]By the reaction and treatment in the same manner as in Example 132
using 5-benzyloxy-N-(4-methoxyphenyl)-1,2,3,4-tetrahydronaphthalene-1-car-
boxamide (0.63 g) and 4-(chloromethyl)-2-methylthiazole (0.30 g) as
starting materials,
5-benzyloxy-N-(4-methoxyphenyl)-N-[(2-methylthiazol-4-yl)methyl]-1,2,3,4--
tetrahydronaphthalene-1-carboxamide (0.64 g) was obtained. By the reaction
and treatment in the same manner as in Example 133 using this compound
(0.50 g), 5-hydroxy-N-(4-methoxyphenyl)-N-[(2-methylthiazol-4-yl)methyl]--
1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.31 g) was obtained.

[0996]By the reaction and treatment in the same manner as in Example 12
using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.57
g) and (4-bromophenyl)[(4-dimethylaminophenyl)methyl]amide (0.61 g) as
starting materials,
5-benzyloxy-N-(4-bromophenyl)-N-[(4-dimethylaminophenyl)methyl]-1,2,3,4-t-
etrahydronaphthalene-1-carboxamide (1.14 g) was obtained. By the reaction
and treatment in the same manner as in Example 133 using this compound,
N-(4-bromophenyl)-N-[(dimethylaminophenyl)methyl]-5-hydroxy-1,2,3,4-tetra-
hydronaphthalene-1-carboxamide (0.23 g) was obtained. melting point:
218-220° C.

Example 207

##STR00226##

[0998]To a solution of 2-tolualdehyde (120 mg) in 1,2-dichloroethane (5
mL) were added 4-isopropylaniline (171 μL), acetic acid (57.2 μL)
and sodium triacetoxyborohydride (445 mg), and the mixture was stirred
for one day. Saturated aqueous sodium hydrogencarbonate (2 mL) was added
to the reaction solution, and the mixture was applied to ExtruteNT-3
(Merck) column and eluted with ethyl acetate (10 mL) 10 min later. The
obtained solution was treated with Sep-Pak Plus Silica (Waters), and the
obtained solution was concentrated under reduced pressure. The obtained
residue was dissolved in methylene chloride (5 mL), and
4-dimethylaminopyridine (30 mg),
7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (250 mg) and
N-cyclohexylcarbodiimide-N'-methylpolystyrene HL (1.5 g) were added. The
mixture was stirred for one day, and the reaction mixture was filtrated
under reduced pressure. The solvent was evaporated under reduced
pressure, and THF (5 mL) and Ambersep 900 OH (800 mg) were added. The
mixture was stirred for 3 hr. The reaction mixture was filtrated under
reduced pressure. Amberlyst 15 (1 g) was added, and the mixture was
stirred for one day. The reaction mixture was filtrated under reduced
pressure, and the solvent was evaporated under reduced pressure. The
residue was purified by silica gel column chromatography to give
N-(4-isopropylphenyl)-7-methoxy-N-(2-tolylethyl)-1,2,3,4-tetrahydronaphth-
alene-1-carboxamide (106 mg).

[0999]MS (ESI) m/z: 428 [MH].sup.+

Example 208

##STR00227##

[1001]By the reaction and treatment in the same manner as in Example 207
using 1-naphthaldehyde (156 mg) as a starting material instead of
2-tolualdehyde,
N-(4-isopropylphenyl)-7-methoxy-N-[(1-naphthyl)methyl]-1,2,3,4-tetrahydro-
naphthalene-1-carboxamide (258.9 mg) was obtained.

[1002]MS (ESI) m/z: 464 [MH].sup.+

Example 209

##STR00228##

[1004]By the reaction and treatment in the same manner as in Example 207
using 2,4-dichlorobenzaldehyde (175 mg) as a starting material instead of
2-tolualdehyde,
N-[(2,4-dichlorophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-te-
trahydronaphthalene-1-carboxamide (258.8 mg) was obtained.

[1005]MS (ESI) m/z: 482 [MH].sup.+

Example 210

##STR00229##

[1007]By the reaction and treatment in the same manner as in Example 207
using 4-nitrobenzaldehyde (151 mg) as a starting material instead of
2-tolualdehyde,
N-(4-isopropylphenyl)-7-methoxy-N-[(4-nitrophenyl)methyl]-1,2,3,4-tetrahy-
dronaphthalene-1-carboxamide (218.9 mg) was obtained.

[1008]MS (ESI) m/z: 459 [MH].sup.+

Example 211

##STR00230##

[1010]By the reaction and treatment in the same manner as in Example 207
using 3-tolualdehyde (120 mg) as a starting material instead of
2-tolualdehyde,
N-(4-isopropylphenyl)-7-methoxy-N-(3-tolylmethyl)-1,2,3,4-tetrahydronapht-
halene-1-carboxamide (145.4 mg) was obtained. MS (ESI) m/z: 428 [MH].sup.+

Example 212

##STR00231##

[1012]By the reaction and treatment in the same manner as in Example 207
using 4-tolualdehyde (120 mg) as a starting material instead of
2-tolualdehyde,
N-(4-isopropylphenyl)-7-methoxy-N-(4-tolylmethyl)-1,2,3,4-tetrahydronapht-
halene-1-carboxamide (116.4 mg) was obtained.

[1013]MS (ESI) m/z: 428 [MH].sup.+

Example 213

##STR00232##

[1015]By the reaction and treatment in the same manner as in Example 207
using 2-fluorobenzaldehyde (124 mg) as a starting material instead of
2-tolualdehyde,
N-[(2-fluorophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrah-
ydronaphthalene-1-carboxamide (148 mg) was obtained.

[1016]MS (ESI) m/z: 432 [MH].sup.+

Example 214

##STR00233##

[1018]By the reaction and treatment in the same manner as in Example 207
using 3-fluorobenzaldehyde (124 mg) as a starting material instead of
2-tolualdehyde,
N-[(3-fluorophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrah-
ydronaphthalene-1-carboxamide (190.9 mg) was obtained.

[1019]MS (ESI) m/z: 432 [MH].sup.+

Example 215

##STR00234##

[1021]By the reaction and treatment in the same manner as in Example 207
using 4-fluorobenzaldehyde (124 mg) as a starting material instead of
2-tolualdehyde,
N-[(4-fluorophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrah-
ydronaphthalene-1-carboxamide (184.2 mg) was obtained.

[1022]MS (ESI) m/z: 432 [MH].sup.+

Example 216

##STR00235##

[1024]By the reaction and treatment in the same manner as in Example 207
using 3-cyanobenzaldehyde (131 mg) as a starting material instead of
2-tolualdehyde,
N-[(3-cyanophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahy-
dronaphthalene-1-carboxamide (191 mg) was obtained.

[1025]MS (ESI) m/z: 439 [MH].sup.+

Example 217

##STR00236##

[1027]By the reaction and treatment in the same manner as in Example 207
using 2,4-dimethylbenzaldehyde (134 mg) as a starting material instead of
2-tolualdehyde,
N-[(2,4-dimethylphenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-te-
trahydronaphthalene-1-carboxamide (119.4 mg) was obtained.

[1028]MS (ESI) m/z: 442 [MH].sup.+

Example 218

##STR00237##

[1030]By the reaction and treatment in the same manner as in Example 207
using 2,5-dimethylbenzaldehyde (134 mg) as a starting material instead of
2-tolualdehyde,
N-[(2,5-dimethylphenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-te-
trahydronaphthalene-1-carboxamide (123.3 mg) was obtained.

[1031]MS (ESI) m/z: 442 [MH].sup.+

Example 219

##STR00238##

[1033]By the reaction and treatment in the same manner as in Example 207
using 2-methoxybenzaldehyde (136 mg) as a starting material instead of
2-tolualdehyde,
N-(4-isopropylphenyl)-7-methoxy-N-[(2-methoxyphenyl)methyl]-1,2,3,4-tetra-
hydronaphthalene-1-carboxamide (190.9 mg) was obtained.

[1034]MS (ESI) m/z: 444 [MH].sup.+

Example 220

##STR00239##

[1036]By the reaction and treatment in the same manner as in Example 207
using 3-methoxybenzaldehyde (136 mg) as a starting material instead of
2-tolualdehyde,
N-(4-isopropylphenyl)-N-[(3-methoxyphenyl)methyl]-7-methoxy-1,2,3,4-tetra-
hydronaphthalene-1-carboxamide (173.1 mg) was obtained.

[1037]MS (ESI) m/z: 444 [MH].sup.+

Example 221

##STR00240##

[1039]By the reaction and treatment in the same manner as in Example 207
using 2-chlorobenzaldehyde (141 mg) as a starting material instead of
2-tolualdehyde,
N-[(2-chlorophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrah-
ydronaphthalene-1-carboxamide (117.5 mg) was obtained.

[1040]MS (ESI) m/z: 448 [MH].sup.+

Example 222

##STR00241##

[1042]By the reaction and treatment in the same manner as in Example 207
using 3-chlorobenzaldehyde (141 mg) as a starting material instead of
2-tolualdehyde,
N-[(3-chlorophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrah-
ydronaphthalene-1-carboxamide (197.6 mg) was obtained.

[1043]MS (ESI) m/z: 448 [MH].sup.+

Example 223

##STR00242##

[1045]By the reaction and treatment in the same manner as in Example 207
using 2,3-difluorobenzaldehyde (142 mg) as a starting material instead of
2-tolualdehyde,
N-[(2,3-difluorophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-te-
trahydronaphthalene-1-carboxamide (130.2 mg) was obtained.

[1046]MS (ESI) m/z: 450 [MH].sup.+

Example 224

##STR00243##

[1048]By the reaction and treatment in the same manner as in Example 207
using 2,4-difluorobenzaldehyde (142 mg) as a starting material instead of
2-tolualdehyde,
N-[(2,4-difluorophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-te-
trahydronaphthalene-1-carboxamide (179.1 mg) was obtained.

[1049]MS (ESI) m/z: 450 [MH].sup.+

Example 225

##STR00244##

[1051]By the reaction and treatment in the same manner as in Example 207
using 2,5-difluorobenzaldehyde (142 mg) as a starting material instead of
2-tolualdehyde,
N-[(2,5-difluorophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-te-
trahydronaphthalene-1-carboxamide (212.6 mg) was obtained.

[1052]MS (ESI) m/z: 450[M].sup.+

Example 226

##STR00245##

[1054]By the reaction and treatment in the same manner as in Example 207
using 2,6-difluorobenzaldehyde (142 mg) as a starting material instead of
2-tolualdehyde,
N-[(2,6-difluorophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-te-
trahydronaphthalene-1-carboxamide (87.8 mg) was obtained.

[1055]MS (ESI) m/z: 450 [MH].sup.+

Example 227

##STR00246##

[1057]By the reaction and treatment in the same manner as in Example 207
using 3,4-difluorobenzaldehyde (142 mg) as a starting material instead of
2-tolualdehyde,
N-[(3,4-difluorophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-te-
trahydronaphthalene-1-carboxamide (126.6 mg) was obtained.

[1058]MS (ESI) m/z: 450 [MH].sup.+

Example 228

##STR00247##

[1060]By the reaction and treatment in the same manner as in Example 207
using 3,5-difluorobenzaldehyde (142 mg) as a starting material instead of
2-tolualdehyde,
N-[(3,5-difluorophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-te-
trahydronaphthalene-1-carboxamide (151 mg) was obtained.

[1061]MS (ESI) m/z: 450 [MH].sup.+

Example 229

##STR00248##

[1063]By the reaction and treatment in the same manner as in Example 207
using 2,3-methylenedioxybenzaldehyde (150 mg) as a starting material
instead of 2-tolualdehyde,
N-[(1,3-dioxaindan-4-yl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-t-
etrahydronaphthalene-1-carboxamide (184.4 mg) was obtained.

[1064]MS (ESI) m/z: 458 [MH].sup.+

Example 230

##STR00249##

[1066]By the reaction and treatment in the same manner as in Example 207
using 4-ethoxybenzaldehyde (150 mg) as a starting material instead of
2-tolualdehyde,
N-[(4-ethoxyphenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrah-
ydronaphthalene-1-carboxamide (177.4 mg) was obtained.

[1067]MS (ESI) m/z: 458 [MH].sup.+

Example 231

##STR00250##

[1069]By the reaction and treatment in the same manner as in Example 207
using 3,4-ethylenedioxybenzaldehyde (164 mg) as a starting material
instead of 2-tolualdehyde,
N-(4-isopropylphenyl)-7-methoxy-N-[(4-oxachroman-6-yl)methyl]-1,2,3,4-tet-
rahydronaphthalene-1-carboxamide (167.6 mg) was obtained.

[1070]MS (ESI) m/z: 472 [NH].sup.+

Example 232

##STR00251##

[1072]By the reaction and treatment in the same manner as in Example 207
using 4-propoxybenzaldehyde (164 mg) as a starting material instead of
2-tolualdehyde,
N-(4-isopropylphenyl)-7-methoxy-N-[(4-propoxyphenyl)methyl]-1,2,3,4-tetra-
hydronaphthalene-1-carboxamide (172.6 mg) was obtained.

[1073]MS (ESI) m/z: 472 [MH].sup.+

Example 233

##STR00252##

[1075]By the reaction and treatment in the same manner as in Example 207
using 3,5-dimethoxybenzaldehyde (166 mg) as a starting material instead
of 2-tolualdehyde,
N-[(3,5-dimethoxyphenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-t-
etrahydronaphthalene-1-carboxamide (199.9 mg) was obtained.

[1076]MS (ESI) m/z: 474 [MH].sup.+

Example 234

##STR00253##

[1078]By the reaction and treatment in the same manner as in Example 207
using 2,3-dimethoxybenzaldehyde (166 mg) as a starting material instead
of 2-tolualdehyde,
N-[(2,3-dimethoxyphenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-t-
etrahydronaphthalene-1-carboxamide (332 mg) was obtained.

[1079]MS (ESI) m/z: 474 [MH].sup.+

Example 235

##STR00254##

[1081]By the reaction and treatment in the same manner as in Example 207
using 2,4-dimethoxybenzaldehyde (166 mg) as a starting material instead
of 2-tolualdehyde,
N-[(2,4-dimethoxyphenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-t-
etrahydronaphthalene-1-carboxamide (69.3 mg) was obtained.

[1082]MS (ESI) m/z: 474 [MH].sup.+

Example 236

##STR00255##

[1084]By the reaction and treatment in the same manner as in Example 207
using 2,5-dimethoxybenzaldehyde (166 mg) as a starting material instead
of 2-tolualdehyde,
N-[(2,5-dimethoxyphenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-t-
etrahydronaphthalene-1-carboxamide (122.5 mg) was obtained.

[1085]MS (ESI) m/z: 474 [NH].sup.+

Example 237

##STR00256##

[1087]By the reaction and treatment in the same manner as in Example 207
using 2,6-dimethoxybenzaldehyde (166 mg) as a starting material instead
of 2-tolualdehyde,
N-[(2,6-dimethoxyphenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-t-
etrahydronaphthalene-1-carboxamide (248.9 mg) was obtained.

[1088]MS (ESI) m/z: 474 [MH].sup.+

Example 238

##STR00257##

[1090]By the reaction and treatment in the same manner as in Example 207
using 3,4-dimethoxybenzaldehyde (166 mg) as a starting material instead
of 2-tolualdehyde,
N-[(3,4-dimethoxyphenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-t-
etrahydronaphthalene-1-carboxamide (96.1 mg) was obtained.

[1091]MS (ESI) m/z: 474 [NH].sup.+

Example 239

##STR00258##

[1093]By the reaction and treatment in the same manner as in Example 207
using 2-trifluoromethylbenzaldehyde (174 mg) as a starting material
instead of 2-tolualdehyde,
N-(4-isopropylphenyl)-7-methoxy-N-[(2-trifluoromethylphenyl)methyl]-1,2,3-
,4-tetrahydronaphthalene-1-carboxamide (179.1 mg) was obtained.

[1094]MS (ESI) m/z: 482 [MH].sup.+

Example 240

##STR00259##

[1096]By the reaction and treatment in the same manner as in Example 207
using 3-trifluoromethylbenzaldehyde (174 mg) as a starting material
instead of 2-tolualdehyde,
N-(4-isopropylphenyl)-7-methoxy-N-[(3-trifluoromethylphenyl)methyl]-1,2,3-
,4-tetrahydronaphthalene-1-carboxamide (186.2 mg) was obtained.

[1097]MS (ESI) m/z: 482 [MH].sup.+

Example 241

##STR00260##

[1099]By the reaction and treatment in the same manner as in Example 207
using 4-trifluoromethylbenzaldehyde (174 mg) as a starting material
instead of 2-tolualdehyde,
N-(4-isopropylphenyl)-7-methoxy-N-[(4-trifluoromethylphenyl)methyl]-1,2,3-
,4-tetrahydronaphthalene-1-carboxamide (207.9 mg) was obtained.

[1100]MS (ESI) m/z: 482 [MH].sup.+

Example 242

##STR00261##

[1102]By the reaction and treatment in the same manner as in Example 207
using 2,3-dichlorobenzaldehyde (175 mg) as a starting material instead of
2-tolualdehyde,
N-[(2,3-dichlorophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-te-
trahydronaphthalene-1-carboxamide (302.3 mg) was obtained.

[1103]MS (ESI) m/z: 482 [MH].sup.+

Example 243

##STR00262##

[1105]By the reaction and treatment in the same manner as in Example 207
using 2,6-dichlorobenzaldehyde (175 mg) as a starting material instead of
2-tolualdehyde,
N-[(2,6-dichlorophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-te-
trahydronaphthalene-1-carboxamide (93.1 mg) was obtained.

[1106]MS (ESI) m/z: 482 [MH].sup.+

Example 244

##STR00263##

[1108]By the reaction and treatment in the same manner as in Example 207
using 3,4-dichlorobenzaldehyde (175 mg) as a starting material instead of
2-tolualdehyde,
N-[(3,4-dichlorophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-te-
trahydronaphthalene-1-carboxamide (288.2 mg) was obtained.

[1109]MS (ESI) m/z: 482 [MH].sup.+

Example 245

##STR00264##

[1111]By the reaction and treatment in the same manner as in Example 207
using 3,5-dichlorobenzaldehyde (175 mg) as a starting material instead of
2-tolualdehyde,
N-[(3,5-dichlorophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-te-
trahydronaphthalene-1-carboxamide (304.4 mg) was obtained.

[1112]MS (ESI) m/z: 482 [MH].sup.+

Example 246

##STR00265##

[1114]By the reaction and treatment in the same manner as in Example 207
using 2-bromobenzaldehyde (185 mg) as a starting material instead of
2-tolualdehyde,
N-[(2-bromophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahy-
dronaphthalene-1-carboxamide (157.6 mg) was obtained.

[1115]MS (ESI) m/z: 492 [MH].sup.+

Example 247

##STR00266##

[1117]By the reaction and treatment in the same manner as in Example 207
using 3-bromobenzaldehyde (185 mg) as a starting material instead of
2-tolualdehyde,
N-[(3-bromophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahy-
dronaphthalene-1-carboxamide (214.4 mg) was obtained.

[1118]MS (ESI) m/z: 492 [MH].sup.+

Example 248

##STR00267##

[1120]By the reaction and treatment in the same manner as in Example 207
using 2,3,4-trimethoxybenzaldehyde (196 mg) as a starting material
instead of 2-tolualdehyde,
N-(4-isopropylphenyl)-7-methoxy-N-[(2,3,4-trimethoxyphenyl)methyl]-1,2,3,-
4-tetrahydronaphthalene-1-carboxamide (365.1 mg) was obtained.

[1121]MS (ESI) m/z: 504 [MH].sup.+

Example 249

##STR00268##

[1123]By the reaction and treatment in the same manner as in Example 207
using 3,4,5-trimethoxybenzaldehyde (196 mg) as a starting material
instead of 2-tolualdehyde,
N-(4-isopropylphenyl)-7-methoxy-N-[(3,4,5-trimethoxyphenyl)methyl]-1,2,3,-
4-tetrahydronaphthalene-1-carboxamide (139.3 mg) was obtained.

[1124]MS (ESI) m/z: 504 [MH].sup.+

Example 250

##STR00269##

[1126]By the reaction and treatment in the same manner as in Example 207
using 3-phenoxybenzaldehyde (198 mg) as a starting material instead of
2-tolualdehyde,
N-(4-isopropylphenyl)-7-methoxy-N-[(3-phenoxyphenyl)methyl]-1,2,3,4-tetra-
hydronaphthalene-1-carboxamide (153.8 mg) was obtained.

[1127]MS (ESI) m/z: 506 [MH].sup.+

Example 251

##STR00270##

[1129]By the reaction and treatment in the same manner as in Example 207
using 4-phenoxybenzaldehyde (198 mg) as a starting material instead of
2-tolualdehyde,
N-(4-isopropylphenyl)-7-methoxy-N-[(4-phenoxyphenyl)methyl]-1,2,3,4-tetra-
hydronaphthalene-1-carboxamide (188.1 mg) was obtained.

[1130]MS (ESI) m/z: 506 [MH].sup.+

Example 252

##STR00271##

[1132]By the reaction and treatment in the same manner as in Example 207
using 2,3,5-trichlorobenzaldehyde (209 mg) as a starting material instead
of 2-tolualdehyde,
N-(4-isopropylphenyl)-7-methoxy-N-[(2,3,5-trichlorophenyl)methyl]-1,2,3,4-
-tetrahydronaphthalene-1-carboxamide (400.7 mg) was obtained.

[1133]MS (ESI) m/z: 516 [MH].sup.+

Example 253

##STR00272##

[1135]By the reaction and treatment in the same manner as in Example 207
using 2,3,6-trichlorobenzaldehyde (209 mg) as a starting material instead
of 2-tolualdehyde,
N-(4-isopropylphenyl)-7-methoxy-N-[(2,3,6-trichlorophenyl)methyl]-1,2,3,4-
-tetrahydronaphthalene-1-carboxamide (112.7 mg) was obtained.

[1136]MS (ESI) m/z: 516 [MH].sup.+

Example 254

##STR00273##

[1138]By the reaction and treatment in the same manner as in Example 82
using 5-benzyloxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-c-
arboxamide (5.94 g) and 1-(tert-butoxycarbonyl)-4-(hydroxymethyl)pyrazole
(2.95 g) as starting materials,
5-benzyloxy-N-(4-isopropylphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrah-
ydronaphthalene-1-carboxamide (3.00 g) was obtained.

[1141]By the reaction and treatment in the same manner as in Example 83
using N-(4-isopropylphenyl)-7-methoxy-N-[(pyrazol-4-yl)methyl]-1,2,3,4-te-
trahydronaphthalene-1-carboxamide (1.32 g) and methyl bromoacetate (0.31
mL) as starting materials, methyl
2-(4-{[N-(4-isopropylphenyl)-N-(7-methoxy-1,2,3,4-tetrahydronaphthalene-1-
-yl)carbonyl)amino]methyl}pyrazol-1-yl)acetate (0.35 g) was obtained.

[1144]Methyl
2-(4-{[N-(4-isopropylphenyl)-N-(7-methoxy-1,2,3,4-tetrahydronaphthalen-1--
ylcarbonyl)amino]methyl}pyrazol-1-yl)acetate (0.34 g) was dissolved in a
mixed solvent (10 mL) of ethanol:THF (2:1), and sodium borohydride (0.11
g) and lithium chloride (0.12 g) were added thereto. The mixture was
stirred at 50° C. for 3 hr. The reaction mixture was concentrated
under reduced pressure and partitioned between water and ethyl acetate.
The organic layer was washed with saturated brine and dried over
anhydrous magnesium sulfate. The solvent was evaporated, and the residue
was purified by silica gel column chromatography to give
N-{[1-(2-hydroxyethyl)pyrazol-4-yl]methyl}-N-(4-isopropylphenyl)-7-methox-
y-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.23 g).

[1147]By the reaction and treatment in the same manner as in Example 106
using N-[(1-ethylpyrazol-4-yl)methyl]-5-hydroxy-N-(4-isopropylphenyl)-1,2-
,3,4-tetrahydronaphthalene-1-carboxamide (1.00 g) and ethyl bromoacetate
(0.40 mL) as starting materials, ethyl
2-(5-{N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)carbamoyl}-5,6-
,7,8-tetrahydronaphthalene-1-yloxy)acetate (1.09 g) was obtained.

[1150]By the reaction and treatment in the same manner as in Example 106
using N-[(1-ethylpyrazol-4-yl)methyl]-6-hydroxy-N-(4-isopropylphenyl)-1,2-
,3,4-tetrahydronaphthalene-1-carboxamide (1.00 g) as a starting material,
ethyl 2-(5-{N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)carbamoy-
l}-5,6,7,8-tetrahydronaphthalene-2-yloxy)acetate (1.11 g) was obtained.

[1153]By the reaction and treatment in the same manner as in Example 106
using N-[(1-ethylpyrazol-4-yl)methyl]-7-hydroxy-N-(4-isopropylphenyl)-1,2-
,3,4-tetrahydronaphthalene-1-carboxamide (1.00 g) as a starting material,
ethyl 2-(8-{N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)carbamoy-
l}-5,6,7,8-tetrahydronaphthalene-2-yloxy)acetate (0.94 g) was obtained.

[1156]By the reaction and treatment in the same manner as in Example 12
using 4-methoxyindan-1-carboxylic acid (0.29 g) and
[(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.37 g) as
starting materials,
N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-4-methoxyindan-1-ca-
rboxamide (0.39 g) was obtained.

[1159]By the reaction and treatment in the same manner as in Example 106
using N-[(1-ethylpyrazol-4-yl)methyl]-5-hydroxy-N-(4-isopropylphenyl)-1,2-
,3,4-tetrahydronaphthalene-1-carboxamide (0.42 g) and
2-chloro-N,N-dimethylethylamine hydrochloride (0.22 g) as starting
materials,
5-[2-(dimethylamino)ethyloxy]-N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopro-
pylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.15 g) was
obtained.

[1162]By the reaction and treatment in the same manner as in Example 256
using ethyl
2-(5-{N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)carbamoyl}-5,6-
,7,8-tetrahydronaphthalene-2-yloxy)acetate (0.56 g) as a starting
material, N-[(1-ethylpyrazol-4-yl)methyl]-6-(2-hydroxyethoxy)-N-(4-isopro-
pylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.46 g) was
obtained. melting point: 137.3° C.

[1165]By the reaction and treatment in the same manner as in Example 256
using ethyl
2-(5-{N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)carbamoyl}-5,6-
,7,8-tetrahydronaphthalene-1-yloxy)acetate (0.60 g) as starting materials,
N-[(1-ethylpyrazol-4-yl)methyl]-5-(2-hydroxyethoxy)-N-(4-isopropylphenyl)-
-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.46 g) was obtained.

[1168]By the reaction and treatment in the same manner as in Example 256
using ethyl
2-(8-{N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)carbamoyl}-5,6-
,7,8-tetrahydronaphthalene-2-yloxy)acetate (0.47 g) as starting materials,
N-[(1-ethylpyrazol-4-yl)methyl]-7-(2-hydroxyethoxy)-N-(4-isopropylphenyl)-
-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.40 g) was obtained.

[1171]By the reaction and treatment in the same manner as in Example 106
using N-[(1-ethylpyrazol-4-yl)methyl]-6-hydroxy-N-(4-isopropylphenyl)-1,2-
,3,4-tetrahydronaphthalene-1-carboxamide (0.42 g) and
2-chloro-N,N-dimethylethylamine hydrochloride (0.22 g) as starting
materials,
6-[2-(dimethylamino)ethoxy]-N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropy-
lphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.19 g) was
obtained.

[1174]By the reaction and treatment in the same manner as in Example 106
using N-[(1-ethylpyrazol-4-yl)methyl]-7-hydroxy-N-(4-isopropylphenyl)-1,2-
,3,4-tetrahydronaphthalene-1-carboxamide (0.42 g) and
2-chloro-N,N-dimethylethylamine hydrochloride (0.22 g) as starting
materials,
7-[2-(dimethylamino)ethoxy]-N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropy-
lphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.15 g) was
obtained.

[1177]By the reaction and treatment in the same manner as in Example 106
using N-[(1-ethylpyrazol-4-yl)methyl]-5-hydroxy-N-(4-isopropylphenyl)-1,2-
,3,4-tetrahydronaphthalene-1-carboxamide (0.42 g) and
3-chloro-N,N-dimethylpropylamine hydrochloride (0.24 g) as starting
materials,
5-[3-(dimethylamino)propoxy]-N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isoprop-
ylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide was obtained. This
was dissolved in ethyl acetate, and oxalic acid (0.12 g) was added. The
precipitated solid was collected by filtration to give
5-[3-(dimethylamino)propoxy]-N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isoprop-
ylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide 3/2 oxalate (0.36
g). melting point: 142.6° C.

[1180]By the reaction and treatment in the same manner as in Example 106
using N-[1-ethylpyrazol-4-yl)methyl]-5-hydroxy-N-(4-isopropylphenyl)-1,2,-
3,4-tetrahydronaphthalene-1-carboxamide (0.46 g) and 1,4-dibromobutane
(1.33 mL) as starting materials,
5-(4-bromobutoxy)-N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-1-
,2,3,4-tetrahydronaphthalene-1-carboxamide (0.52 g) was obtained.

[1183]To a solution of
5-(4-bromobutoxy)-N-[(l-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-1-
,2,3,4-tetrahydronaphthalene-1-carboxamide (0.52 g) in acetonitrile (10
mL) were added dimethylamine hydrochloride (0.69 g) and potassium
carbonate (1.30 g), and the mixture was heated under reflux for 1.5 hr.
The reaction mixture was concentrated under reduced pressure, and the
residue was partitioned between water and chloroform. The organic layer
was washed with saturated brine and dried over anhydrous sodium sulfate.
The solvent was evaporated, and the residue was purified by silica gel
column chromatography to give
5-[4-(dimethylamino)butoxy]-N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropy-
lphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.27 g).

[1186]By the reaction and treatment in the same manner as in Example 12
using 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.35 g) and
(4-isopropylphenyl)[(1-phenylpyrazol-4-yl)methyl]amine (0.58 g) as
starting materials,
N-(4-isopropylphenyl)-N-[(1-phenylpyrazol-4-yl)methyl]-1,2,3,4-tetrahydro-
naphthalene-1-carboxamide (0.42 g) was obtained.

[1189]To a solution of
5-benzyloxy-N-(4-isopropylphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrah-
ydronaphthalene-1-carboxamide (0.27 g) in methylene chloride (2 mL) were
added tetra-n-butylammonium hydrogensulfate (0.66 g),
2-(chloromethyl)pyridine hydrochloride (0.19 g) and 1 mol/L-aqueous
sodium hydroxide solution (2.26 mL), and the mixture was stirred at room
temperature for one day. The reaction mixture was partitioned between
water and chloroform. The organic layer was washed with saturated brine
and dried over anhydrous magnesium sulfate. The solvent was evaporated
and the residue was purified by silica gel column chromatography to give
5-benzyloxy-N-(4-isopropylphenyl)-N-{[1-(2-pyridylmethyl)pyrazol-4-yl]met-
hyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.19 g).

[1192]By the reaction and treatment in the same manner as in Example 101
using 5-benzyloxy-N-(4-isopropylphenyl)-N-{[1-(2-pyridylmethyl)pyrazol-4--
yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.19 g) as a
starting material,
5-hydroxy-N-(4-isopropylphenyl)-N-{[1-(2-pyridylmethyl)pyrazol-4-yl]methy-
l}-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.08 g) was
obtained. MS (ESI) m/z: 481 [MH].sup.+

[1195]By the reaction and treatment in the same manner as in Example 271
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,-
2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.36 g) and
benzyl bromide (0.18 mL) as starting materials,
5-benzyloxy-N-[(1-benzylpyrazol-4-yl)methyl]-N-(6-isopropylpyridin-3-yl)--
1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.34 g) was obtained.

[1198]By the reaction and treatment in the same manner as in Example 101
using 5-benzyloxy-N-[(1-benzylpyrazol-4-yl)methyl]-N-(6-isopropylpyridin--
3-yl)-1,2,3,4-tetrahydronaphthalene-1-5-carboxamide (0.34 g) as starting
materials,
N-[(1-benzylpyrazol-4-yl)methyl]-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,-
2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.27 g) was
obtained.

[1201]By the reaction and treatment in the same manner as in Example 271
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,-
2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and
2-(chloromethyl)pyridine hydrochloride (0.49 g) as starting materials,
5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(2-pyridylmethyl)pyrazol-4--
yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.74 g) was
obtained.

[1204]By the reaction and treatment in the same manner as in Example 139
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(1-(2-pyridylmethyl)pyra-
zol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.72 g) as a
starting material,
5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(2-pyridylmethyl)pyrazol-4-yl-
]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide dihydrochloride (0.56
g) was obtained.

[1208]By the reaction and treatment in the same manner as in Example 271
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,-
2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and
3-(chloromethyl)pyridine hydrochloride (0.49 g) as starting materials,
5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(3-pyridylmethyl)pyrazol-4--
yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.68 g) was
obtained.

[1211]By the reaction and treatment in the same manner as in Example 139
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(3-pyridylmethyl)pyra-
zol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.66 g) as a
starting material,
5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(3-pyridylmethyl)pyrazol-4-yl-
]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide dihydrochloride (0.51
g) was obtained.

[1215]By the reaction and treatment in the same manner as in Example 271
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,-
2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and
4-fluorobenzyl chloride (0.36 mL) as starting materials,
5-benzyloxy-N-({1-[(4-fluorophenyl)methyl]pyrazol-4-yl}methyl)-N-(6-isopr-
opylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.76 g) was
obtained.

[1218]By the reaction and treatment in the same manner as in Example 139
using 5-benzyloxy-N-({1-[(4-fluorophenyl)methyl]pyrazol-4-yl}methyl)-N-(6-
-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.76
g) as a starting material,
N-({1-[(4-fluorophenyl)methyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(6-isoprop-
ylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride
(0.59 g) was obtained.

[1222]By the reaction and treatment in the same manner as in Example 271
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,-
2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and
4-chlorobenzyl chloride (0.48 g) as starting materials,
5-benzyloxy-N-({1-[(4-chlorophenyl)methyl]pyrazol-4-yl}methyl)-N-(6-isopr-
opylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.76 g) was
obtained.

[1225]By the reaction and treatment in the same manner as in Example 139
using 5-benzyloxy-N-({1-[(4-chlorophenyl)methyl]pyrazol-4-yl}methyl)-N-(6-
-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.76
g) as a starting material,
N-({1-[(4-chlorophenyl)methyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(6-isoprop-
ylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride
(0.65 g) was obtained.

[1229]By the reaction and treatment in the same manner as in Example 271
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,-
2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and
4-(trifluoromethyl)benzyl chloride (0.48 g) as starting materials,
5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(4-trifluoromethylphenyl)m-
ethyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide
(0.84 g) was obtained.

[1232]By the reaction and treatment in the same manner as in Example 139
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(4-trifluoromethylph-
enyl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxami-
de (0.83 g) as a starting material,
5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(4-trifluoromethylphenyl)met-
hyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide
hydrochloride (0.67 g) was obtained. MS (ESI) m/z: 549 [MH].sup.+

[1235]By the reaction and treatment in the same manner as in Example 271
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,-
2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and
3-chloromethyl-6-isopropylpyridine (0.51 g) as starting materials,
5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(6-isopropylpyridin-3-yl)m-
ethyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide
(0.77 g) was obtained.

[1238]By the reaction and treatment in the same manner as in Example 139
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(6-isopropylpyridin--
3-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxami-
de (0.76 g) as a starting material,
5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(6-isopropylpyridin-3-yl)met-
hyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide
dihydrochloride (0.57 g) was obtained. MS (ESI) m/z: 524 [MH].sup.+

[1241]By the reaction and treatment in the same manner as in Example 271
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,-
2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and
5-(chloromethyl)-2,4-dimethylthiazole (0.49 g) as starting materials,
5-benzyloxy-N-({1-[(2,4-dimethylthiazol-5-yl)methyl]pyrazol-4-yl}methyl)--
N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide
(0.92 g) was obtained.

[1244]By the reaction and treatment in the same manner as in Example 139
using 5-benzyloxy-N-({1-[(2,4-dimethylthiazol-5-yl)
methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydr-
onaphthalene-1-carboxamide (0.91 g) as a starting material,
N-({1-[(2,4-dimethylthiazol-5-yl)methyl]pyrazol-4-yl}methyl)-5-hydroxy-N--
(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide
hydrochloride (0.35 g) was obtained.

[1248]By the reaction and treatment in the same manner as in Example 271
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,-
2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and
4-methoxybenzyl chloride (0.41 mL) as starting materials,
5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(4-methoxyphenyl)methyl]py-
razol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.69 g)
was obtained.

[1251]By the reaction and treatment in the same manner as in Example 101
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(4-methoxyphenyl)met-
hyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.69
g) as a starting material,
5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(4-methoxyphenyl)methyl]pyra-
zol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride
(0.54 g) was obtained.

[1255]By the reaction and treatment in the same manner as in Example 271
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,-
2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and
4-chloromethyl-1-ethylpyrazole (0.43 g) as starting materials,
5-benzyloxy-N-({1-[(1-ethylpyrazol-4-yl)methyl]pyrazol-4-yl}methyl)-N-(6--
isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.58
g) was obtained.

[1258]By the reaction and treatment in the same manner as in Example 139
using 5-benzyloxy-N-({1-[(1-ethylpyrazol-4-yl)methyl]pyrazol-4-yl}methyl)-
-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide
(0.44 g) as a starting material,
N-({1-[(1-ethylpyrazol-4-yl)methyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(6-is-
opropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide
hydrochloride (0.34 g) was obtained. MS (ESI) m/z: 499 [MH].sup.+

[1261]By the reaction and treatment in the same manner as in Example 271
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,-
2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.66 g) and
methyl 4-(bromomethyl)benzoate (0.31 g) as starting materials, methyl
4-[(4-{[N-(5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-ylcarbonyl)-N-(6-i-
sopropylpyridin-3-yl)amino]methyl}pyrazol-1-yl)methyl]benzoate (0.61 g)
was obtained.

[1264]By the reaction and treatment in the same manner as in Example 101
using methyl
4-[(4-{[N-(5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-ylcarbonyl)-N-(6-i-
sopropylpyridin-3-yl)amino]methyl}pyrazol-1-yl)methyl]benzoate (0.61 g) as
a starting material, methyl
4-[(4-{[N-(5-hydroxy-1,2,3,4-tetrahydronaphthalene-1-ylcarbonyl)-N-(6-iso-
propylpyridin-3-yl)amino]methyl}pyrazol-1-yl)methyl]benzoate hydrochloride
(0.51) was obtained.

[1268]Methyl
4-[(4-{[N-(5-hydroxy-1,2,3,4-tetrahydronaphthalene-1-ylcarbonyl)-N-(6-iso-
propylpyridin-3-yl)amino]methyl}pyrazol-1-yl)methyl]benzoate (0.36 g) was
dissolved in a mixed solvent (4 mL) of ethanol: 1 mol/L-aqueous sodium
hydroxide solution (1:1), and the mixture was stirred at room temperature
for one day. The reaction mixture was concentrated under reduced
pressure, and the residue was partitioned between water and toluene.
Citric acid was added to the aqueous layer until the mixture is
acidified. The aqueous layer was extracted with ethyl acetate. The
organic layer was washed with saturated brine and dried over anhydrous
magnesium sulfate. The solvent was evaporated, and the residue was
dissolved in ethyl acetate. Thereto was added 4 mol/L-HCl/dioxane. The
precipitated solid was collected by filtration to give
4-[(4-{[N-(5-hydroxy-1,2,3,4-tetrahydronaphthalene-1-ylcarbonyl)-N-(6-iso-
propylpyridin-3-yl)amino]methyl}pyrazol-1-yl)methyl]benzoic acid
hydrochloride (0.27 g).

[1272]By the reaction and treatment in the same manner as in Example 271
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,-
2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and
4-bromobenzyl chloride (0.75 g) as starting materials,
5-benzyloxy-N-({1-[(4-bromophenyl)methyl]pyrazol-4-yl}methyl)-N-(6-isopro-
pylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.83 g) was
obtained.

[1275]By the reaction and treatment in the same manner as in Example 139
using 5-benzyloxy-N-({1-[(4-bromophenyl)methyl]pyrazol-4-yl}methyl)-N-(6--
isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.83
g) as a starting material,
N-({1-[(4-bromophenyl)methyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(6-isopropy-
lpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride
(0.68 g) was obtained.

[1279]By the reaction and treatment in the same manner as in Example 271
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,-
2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and
3-chlorobenzyl chloride (0.38 mL) as starting materials,
5-benzyloxy-N-({1-[(3-chlorophenyl)methyl]pyrazol-4-yl}methyl)-N-(6-isopr-
opylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.77 g) was
obtained.

[1282]By the reaction and treatment in the same manner as in Example 139
using 5-benzyloxy-N-({1-[(3-chlorophenyl)methyl]pyrazol-4-yl}methyl)-N-(6-
-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.77
g) as a starting material,
N-({1-[(3-chlorophenyl)methyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(6-isoprop-
ylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride
(0.62 g) was obtained.

[1286]By the reaction and treatment in the same manner as in Example 271
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,-
2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and
2-chlorobenzyl chloride (0.38 mL) as starting materials,
5-benzyloxy-N-({1-[(2-chlorophenyl)methyl]pyrazol-4-yl}methyl)-N-(6-isopr-
opylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.77 g) was
obtained.

[1289]By the reaction and treatment in the same manner as in Example 139
using 5-benzyloxy-N-({1-[(2-chlorophenyl)methyl]pyrazol-4-yl}methyl)-N-(6-
-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.76
g) as a starting material,
N-({1-[(2-chlorophenyl)methyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(6-isoprop-
ylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride
(0.61 g) was obtained.

[1293]By the reaction and treatment in the same manner as in Example 271
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,-
2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and
4-methylbenzyl chloride (0.42 g) as starting materials,
5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(4-methylphenyl)methyl]pyr-
azol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.66 g) was
obtained.

[1296]By the reaction and treatment in the same manner as in Example 139
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(4-methylphenyl)meth-
yl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.66
g) as starting materials,
5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(4-methylphenyl)methyl]pyraz-
ol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride
(0.55 g) was obtained.

[1300]By the reaction and treatment in the same manner as in Example 271
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,-
2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and
2-(chloromethyl)-5-methylpyridine (0.43 g) as starting materials,
5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(5-methylpyridin-2-yl)meth-
yl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.71
g) was obtained.

[1303]By the reaction and treatment in the same manner as in Example 139
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(5-methylpyridin-2-y-
l)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide
(0.71 g) as a starting material,
5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(5-methylpyridin-2-yl)methyl-
]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide
dihydrochloride (0.62 g) was obtained. MS (ESI) m/z: 496 [MH].sup.+

[1306]By the reaction and treatment in the same manner as in Example 271
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,-
2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and
6-chloromethyl-3-methoxypyridine (0.47 g) as starting materials,
5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(5-methoxypyridin-2-yl)met-
hyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.63
g) was obtained.

[1309]By the reaction and treatment in the same manner as in Example 101
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(5-methoxypyridin-2--
yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide
(0.61 g) as a starting material,
5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(5-methoxypyridin-2-yl)methy-
l]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide
dihydrochloride (0.46 g) was obtained. MS (ESI) m/z: 512 [MH].sup.+

[1312]By the reaction and treatment in the same manner as in Example 271
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,-
2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and
2-chloromethyl-6-methylpyridine (0.43 g) as starting materials,
5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(6-methylpyridin-2-yl)meth-
yl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.75
g) was obtained.

[1315]By the reaction and treatment in the same manner as in Example 139
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(6-methylpyridin-2-y-
l)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide
(0.74 g) as a starting material,
5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(6-methylpyridin-2-yl)methyl-
]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide
dihydrochloride (0.63 g) was obtained. MS (ESI) m/z: 496 [MH].sup.+

[1318]By the reaction and treatment in the same manner as in Example 271
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,-
2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and
2-(chloromethyl)-4-methylpyridine (0.53 g) as starting materials,
5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(4-methylpyridin-2-yl)meth-
yl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.67
g) was obtained.

[1321]By the reaction and treatment in the same manner as in Example 139
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(4-methylpyridin-2-y-
l)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide
(0.67 g) as a starting material,
5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(4-methylpyridin-2-yl)methyl-
]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide
dihydrochloride (0.57 g) was obtained. MS (ESI) m/z: 496 [MH].sup.+

[1324]By the reaction and treatment in the same manner as in Example 82
using 1-(tert-butyloxycarbonyl)-4-(hydroxymethyl)pyrazole (1.41 g) and
5-benzyloxy-8-fluoro-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphth-
alene-1-carboxamide (2.83 g) as starting materials,
5-benzyloxy-8-fluoro-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-
-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (1.62 g) was
obtained.

[1325]melting point: 194.7° C.

Example 313

##STR00332##

[1327]By the reaction and treatment in the same manner as in Example 271
using 5-benzyloxy-8-fluoro-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)m-
ethyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.79 g) and
2-(chloromethyl)pyridine hydrochloride (0.49 g) as starting materials,
5-benzyloxy-8-fluoro-N-(6-isopropylpyridin-3-yl)-N-{[1-(2-pyridylmethyl)p-
yrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.69 g)
was obtained.

[1330]By the reaction and treatment in the same manner as in Example 139
using 5-benzyloxy-8-fluoro-N-(6-isopropylpyridin-3-yl)-N-{[1-(2-pyridylme-
thyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide
(0.69 g) as a starting material,
8-fluoro-5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(2-pyridylmethyl)pyr-
azol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide
dihydrochloride (0.69 g) was obtained. MS (ESI) m/z: 500 [MH].sup.+

[1333]By the reaction and treatment in the same manner as in Example 271
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,-
2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and
3-(benzyloxy)-6-(chloromethyl)pyridine (0.81 g) as starting materials,
5-benzyloxy-N-({1-[(5-(benzyloxy)pyridin-2-yl)methyl]pyrazol-4-yl}methyl)-
-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide
(0.75 g) was obtained.

[1339]By the reaction and treatment in the same manner as in Example 271
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,-
2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and
2-chloromethyl-5-ethylpyridine (0.58 g) as starting materials,
5-benzyloxy-N-({1-[(5-ethylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-N-(6--
isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.75
g) was obtained.

[1342]By the reaction and treatment in the same manner as in Example 271
using 5-benzyloxy-N-({1-[(5-ethylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-
-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide
(0.75 g) as a starting material,
N-({1-[(5-ethylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(6-is-
opropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide
dihydrochloride (0.61 g) was obtained.

[1346]By the reaction and treatment in the same manner as in Example 271
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,-
2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and
2-chloromethyl-3-methylpyridine (0.53 g) as starting materials,
5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(3-methylpyridin-2-yl)meth-
yl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.75
g) was obtained.

[1349]By the reaction and treatment in the same manner as in Example 139
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(3-methylpyridin-2-y-
l)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide
(0.74 g) as a starting material,
5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(3-methylpyridin-2-yl)methyl-
]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide
dihydrochloride (0.65 g) was obtained.

[1353]By the reaction and treatment in the same manner as in Example 271
using 5-benzyloxy-8-fluoro-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)m-
ethyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.81 g)
and 2-chloromethyl-4-methylpyridine (0.54 g) as starting materials,
5-benzyloxy-8-fluoro-N-(6-isopropylpyridin-3-yl)-N-({1-[(4-methylpyridin--
2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxami-
de (0.77 g) was obtained.

[1356]By the reaction and treatment in the same manner as in Example 139
using 5-benzyloxy-8-fluoro-N-(6-isopropylpyridin-3-yl)-N-({1-[(4-methylpy-
ridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-car-
boxamide (0.76 g) as a starting material,
8-fluoro-5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(4-methylpyridin-2--
yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide
dihydrochloride (0.64 g) was obtained.

[1360]By the reaction and treatment in the same manner as in Example 271
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,-
2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and
2-chloromethyl-4-trifluoromethylpyridine (0.67 g) as starting materials,
5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(4-trifluoromethylpyridin--
2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxami-
de (0.79 g) was obtained.

[1366]By the reaction and treatment in the same manner as in Example 271
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,-
2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and
5-butyl-2-chloromethylpyridine (0.66 g) as starting materials,
5-benzyloxy-N-({1-[(5-butylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-N-(6--
isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.76
g) was obtained.

[1369]By the reaction and treatment in the same manner as in Example 139
using 5-benzyloxy-N-({1-[(5-butylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-
-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide
(0.76 g) as a starting material,
N-({1-[(5-butylpyridin-5-yl)methyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(6-is-
opropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide
dihydrochloride (0.62 g) was obtained.

[1373]By the reaction and treatment in the same manner as in Example 271
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,-
2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and
3-chloromethyl-2,6-dimethoxypyridine (0.56 g) as starting materials,
5-benzyloxy-N-({1-[(2,6-dimethoxypyridin-3-yl)methyl]pyrazol-4-yl}methyl)-
-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide
(0.69 g) was obtained.

[1379]By the reaction and treatment in the same manner as in Example 132
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthale-
ne-1-carboxamide (1.20 g) and 4-chloromethyl-2-ethylthiazole (0.49 g) as
starting materials,
5-benzyloxy-N-[(2-ethylthiazol-4-yl)methyl]-N-(6-isopropylpyridin-3-yl)-1-
,2,3,4-tetrahydronaphthalene-1-carboxamide (1.30 g) was obtained.

[1382]By the reaction and treatment in the same manner as in Example 139
using 5-benzyloxy-N-[(2-ethylthiazol-4-yl)methyl]-N-(6-isopropylpyridin-3-
-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.28 g) as a starting
material, N-[(2-ethylthiazol-4-yl)methyl]-5-hydroxy-N-(6-isopropylpyridin-
-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.85 g)
was obtained.

[1386]By the reaction and treatment in the same manner as in Example 271
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,-
2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and
4-chloromethyl-2-ethylthiazole (0.49 g) as starting materials,
5-benzyloxy-N-({1-[(2-ethylthiazol-4-yl}methyl]pyrazol-4-yl)methyl)-N-(6--
isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.66
g) was obtained.

[1389]By the reaction and treatment in the same manner as in Example 139
using 5-benzyloxy-N-({1-[(2-ethylthiazol-4-yl)methyl]pyrazol-4-yl}methyl)-
-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide
(0.65 g) as a starting material,
N-({1-[(2-ethylthiazol-4-yl)methyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(6-is-
opropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide
hydrochloride (0.56 g) was obtained. MS (ESI) m/z: 516 [MH]+

[1399]By the reaction and treatment in the same manner as in Example 334
using N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrah-
ydronaphthalene-1-carboxamide hydrochloride (0.95 g) and
2-chloromethyl-5-methoxypyridine (0.83 g) as starting materials,
N-(6-isopropylpyridin-3-yl)-N-({1-[(5-methoxypyridin-2-yl)methyl]pyrazol--
4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide dihydrochloride
(0.97 g) was obtained.

[1403]By the reaction and treatment in the same manner as in Example 271
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,-
2,3,4-tetrahydronaphthalene-1-carboxamide (0.78 g) and
6-chloromethyl-2-(dimethylamino)pyridine (0.46 g) as starting materials,
5-benzyloxy-N-({1-[(6-dimethylaminopyridin-2-yl)methyl]pyrazol-4-yl}methy-
l)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide
(0.43 g) was obtained.

[1409]By the reaction and treatment in the same manner as in Example 271
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,-
2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and
3-(dimethylamino)benzyl chloride (0.51 g) as starting materials,
5-benzyloxy-N-({1-[3-(dimethylaminophenyl)methyl]pyrazol-4-yl}methyl)-N-(-
6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.46
g) was obtained.

[1412]By the reaction and treatment in the same manner as in Example 101
using 5-benzyloxy-N-({1-[3-(dimethylaminophenyl)methyl]pyrazol-4-yl}methy-
l)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide
(0.46 g) as a starting material,
N-({1-[3-(dimethylaminophenyl)methyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(6--
isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide
dihydrochloride (0.33 g) was obtained. MS (ESI) m/z: 524 [MH].sup.+

[1415]By the reaction and treatment in the same manner as in Example 271
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,-
2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and
2-(dimethylamino)benzyl chloride (0.51 g) as starting materials,
5-benzyloxy-N-({1-[(2-(dimethylamino)phenyl)methyl]pyrazol-4-yl}methyl)-N-
-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide
(0.43 g) was obtained.

[1418]By the reaction and treatment in the same manner as in Example 101
using 5-benzyloxy-N-({1-[(2-(dimethylamino)phenyl)methyl]pyrazol-4-yl}met-
hyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxami-
de (0.43 g) as a starting material,
N-({1-[(2-(dimethylamino)phenyl)methyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(-
6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide
dihydrochloride (0.32 g) was obtained. MS (ESI) m/z: 524 [MH].sup.+

[1421]By the reaction and treatment in the same manner as in Example 82
using N-(4-isopropylphenyl)-8-nitrochroman-4-carboxamide (4.1 g) and
1-(tert-butyloxycarbonyl)-4-(hydroxymethyl)pyrazole (2.4 g) as starting
materials,
N-(4-isopropylphenyl)-8-nitro-N-[(pyrazol-4-yl)methyl]chroman-4-carboxami-
de (2.9 g) was obtained.

[1424]By the reaction and treatment in the same manner as in Example 271
using N-(4-isopropylphenyl)-8-nitro-N-[(pyrazol-4-yl)methyl]chroman-4-car-
boxamide (2.9 g) and ethyl iodide (1.1 mL) as starting materials,
N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-8-nitrochroman-4-ca-
rboxamide (2.9 g) was obtained.

[1427]To a mixed solvent of ethanol (43 mL) and water (18 mL) were added
iron (0.43 g) and ammonium chloride (0.06 g), and a solution of
N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-8-nitrochroman-4-ca-
rboxamide (0.9 g) in ethanol (10 mL) was added dropwise with heating and
stirring at 50° C.-70° C. After stirring at 50°
C.-70° C. for 3 hr, the reaction mixture was partitioned between
water and ethyl acetate. The organic layer was washed with saturated
brine and dried over magnesium sulfate. The solvent was evaporated, and
the residue was purified by silica gel column chromatography to give
8-amino-N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)chroman-4-ca-
rboxamide (0.66 g).

[1430]By the reaction and treatment in the same manner as in Example 82
using 4-benzyloxy-N-(2,4-dimethoxyphenyl)indan-1-carboxamide (0.96 g) and
1-(tert-butyloxycarbonyl)-4-(hydroxymethyl)pyrazole (0.47 g) as starting
materials,
4-benzyloxy-N-(2,4-dimethoxyphenyl)-N-[(pyrazol-4-yl)methyl]indan-1-carbo-
xamide (0.43 g) was obtained. By the reaction and treatment in the same
manner as in Example 271 using this compound (0.43 g) and ethyl iodide
(0.28 mL),
4-benzyloxy-N-(2,4-dimethoxyphenyl)-N-[(1-ethylpyrazol-4-yl)methyl]indan--
1-carboxamide (0.36 g) was obtained. By the reaction and treatment in the
same manner as in Example 17 using this compound (0.36 g),
N-(2,4-dimethoxyphenyl)-N-[(1-ethylpyrazol-4-yl)methyl]-4-hydroxyindan-1--
carboxamide (0.21 g) was obtained.

[1434]By the reaction and treatment in the same manner as in Example 12
using 7-fluoro-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.41 g)
and [(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.51 g) as
starting materials,
N-[(1-ethylpyrazol-4-yl)methyl]-7-fluoro-N-(4-isopropylphenyl)-1,2,3,4-te-
trahydronaphthalene-1-carboxamide (0.33 g) was obtained.

[1437]By the reaction and treatment in the same manner as in Example 12
using 8-cyanochroman-4-carboxylic acid (0.7 g) and
[(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.84 g) as
starting materials,
8-cyano-N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)chroman-4-ca-
rboxamide (1.2 g) was obtained.

[1440]By the reaction and treatment in the same manner as in Example 82
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-8-methyl-1,2,3,4-tetrahydro-
naphthalene-1-carboxamide (1.75 g) and
1-(tert-butyloxycarbonyl)-4-(hydroxymethyl)pyrazole (0.84 g) as starting
materials,
5-benzyloxy-N-(6-isopropylpyridin-3-yl)-8-methyl-N-[(pyrazol-4-yl)methyl]-
-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.22 g) was obtained.

[1444]By the reaction and treatment in the same manner as in Example 271
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-8-methyl-N-[(pyrazol-4-yl)m-
ethyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.5 g) and
2-chloromethyl-4-methylpyridine hydrochloride (0.36 g) as starting
materials,
5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(4-methylpyridin-2-yl)meth-
yl]pyrazol-4-yl}methyl)-8-methyl-1,2,3,4-tetrahydronaphthalene-1-carboxami-
de (0.45 g) was obtained.

[1450]By the reaction and treatment in the same manner as in Example 142
using 2-ethyl-5-hydroxymethyl-4-methylthiazole (0.63 g) and
5-benzyloxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-c-
arboxamide (1.8 g) as starting materials,
5-benzyloxy-N-[(2-ethyl-4-methylthiazol-5-yl)methyl]-N-(6-isopropylpyridi-
n-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.3 g) was obtained.

[1451]MS (ESI) m/z: 540 [MH].sup.+

Example 352

##STR00371##

[1453]By the reaction and treatment in the same manner as in Example 139
using 5-benzyloxy-N-[(2-ethyl-4-methylthiazol-5-yl)methyl]-N-(6-isopropyl-
pyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.3 g) as a
starting material,
N-[(2-ethyl-4-methylthiazol-5-yl)methyl]-5-hydroxy-N-(6-isopropylpyridin--
3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.83 g)
was obtained.

[1457]By the reaction and treatment in the same manner as in Example 142
using 2-ethyl-5-hydroxymethyl-4-trifluoromethylthiazole (0.63 g) and
5-benzyloxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-c-
arboxamide (1.2 g) as starting materials,
5-benzyloxy-N-[(2-ethyl-4-trifluoromethylthiazol-5-yl)methyl]-N-(6-isopro-
pylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.4 g) was
obtained.

[1460]By the reaction and treatment in the same manner as in Example 133
using 5-benzyloxy-N-[(2-ethyl-4-trifluoromethylthiazol-5-yl)methyl]-N-(6--
isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.4 g)
as a starting material,
N-[(2-ethyl-4-trifluoromethylthiazol-5-yl)methyl]-5-hydroxy-N-(6-isopropy-
lpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.22 g) was
obtained.

[1464]To a solution of
5-benzyloxy-N-(4-isopropylphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrah-
ydronaphthalene-1-carboxamide (0.35 g) in dimethylformamide were added
2-chloro-N,N-dimethylethylamine hydrochloride (0.12 g) and sodium hydride
(0.035 g), and the mixture was stirred for one day. The reaction mixture
was partitioned between water and ethyl acetate. The organic layer was
washed with saturated brine and dried over magnesium sulfate. The solvent
was evaporated, and the obtained residue was reacted and treated in the
same manner as in Example 17 to give
N-({1-[2-(dimethylamino)ethyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(4-isoprop-
ylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.18 g). melting
point: 92° C.

Example 356

##STR00375##

[1466]By the reaction and treatment in the same manner as in Example 17
using 5-benzyloxy-N-(4-isopropylphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4--
tetrahydronaphthalene-1-carboxamide (0.36 g) as a starting material,
5-hydroxy-N-(4-isopropylphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahyd-
ronaphthalene-1-carboxamide (0.14 g) was obtained. melting point:
247° C.

Example 357

##STR00376##

[1468]By the reaction and treatment in the same manner as in Example 83
using 5-benzyloxy-N-(4-isopropylphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4--
tetrahydronaphthalene-1-carboxamide (0.41 g) and isopropyl iodide (0.16
mg) as starting materials,
5-benzyloxy-N-(4-isopropylphenyl)-N-[(1-isopropylpyrazol-4-yl)methyl]-1,2-
,3,4-tetrahydronaphthalene-1-carboxamide (0.47 g) was obtained. By the
reaction and treatment of this compound, in the same manner as in Example
17 5-hydroxy-N-(4-isopropylphenyl)-N-[(1-isopropylpyrazol-4-yl)methyl]-1,-
2,3,4-tetrahydronaphthalene-1-carboxamide (0.22 g) was obtained. melting
point: 185° C.

Example 358

##STR00377##

[1470]By the reaction and treatment in the same manner as in Example 83
using 5-benzyloxy-N-(4-isopropylphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4--
tetrahydronaphthalene-1-carboxamide (0.50 mg) and bromocyclopentane (0.12
mL) as starting materials,
5-benzyloxy-N-[(1-cyclopentylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-1-
,2,3,4-tetrahydronaphthalene-1-carboxamide (0.54 g) was obtained. By the
reaction and treatment of this compound in the same manner as in Example
17, N-[(1-cyclopentylpyrazol-4-yl)methyl]-5-hydroxy-N-(4-isopropylphenyl)-
-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.27 g) was obtained.
melting point: 173° C.

Example 359

##STR00378##

[1472]By the reaction and treatment in the same manner as in Example 83
using 5-benzyloxy-N-(4-isopropylphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4--
tetrahydronaphthalene-1-carboxamide (0.52 g) and methyl iodide (0.073 mL)
as starting materials,
5-benzyloxy-N-(4-isopropylphenyl)-N-[(1-methylpyrazol-4-yl)methyl]-1,2,3,-
4-tetrahydronaphthalene-1-carboxamide (0.49 g) was obtained. By the
reaction and treatment of this compound in the same manner as in Example
17, 5-hydroxy-N-(4-isopropylphenyl)-N-[(1-methylpyrazol-4-yl)methyl]-1,2,-
3,4-tetrahydronaphthalene-1-carboxamide (0.33 g) was obtained. melting
point: 215° C.

Example 360

##STR00379##

[1474]By the reaction and treatment in the same manner as in Example 83
using 5-benzyloxy-N-(4-isopropylphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4--
tetrahydronaphthalene-1-carboxamide (0.50 g) and 1-bromopropane (0.1 mL)
as starting materials,
5-benzyloxy-N-(4-isopropylphenyl)-N-[(1-propylpyrazol-4-yl)methyl]-1,2,3,-
4-tetrahydronaphthalene-1-carboxamide (0.52 g) was obtained. By the
reaction and treatment of this compound in the same manner as in Example
17, 5-hydroxy-N-(4-isopropylphenyl)-N-[(1-propylpyrazol-4-yl)methyl]-1,2,-
3,4-tetrahydronaphthalene-1-carboxamide (0.31 g) was obtained. melting
point: 161° C.

Example 361

##STR00380##

[1476]By the reaction and treatment in the same manner as in Example 83
using 5-benzyloxy-N-(4-isopropylphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4--
tetrahydronaphthalene-1-carboxamide (1.12 g) and ethyl bromoacetate (0.31
mL), ethyl
2-(4-{[N-(5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-ylcarbonyl)-N-(4-iso-
propylphenyl)amino]methyl}pyrazol-1-yl)acetate (0.66 g) was obtained. This
compound was dissolved in ethanol (20 mL), and 1 mol/L-aqueous sodium
hydroxide solution (1.22 mL) was added. The mixture was stirred at room
temperature for 1 hr. To the reaction mixture was added 1
mol/L-hydrochloric acid (1.22 mL), and the mixture was extracted with
ethyl acetate. The organic layer was washed with saturated brine and
dried over anhydrous magnesium sulfate. The solvent was evaporated. By
the reaction and treatment of the obtained residue in the same manner as
in Example 17 (0.58 g),
2-(4-{[N-(5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-ylcarbonyl)-N-(4-iso-
propylphenyl)amino]methyl}pyrazol-1-yl)acetic acid (0.23 g) was obtained.
melting point: 180-182° C.

Example 362

##STR00381##

[1478]Ethyl
2-(4-{[N-(5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-ylcarbonyl)-N-(4-iso-
propylphenyl)amino]methyl}pyrazol-1-yl)acetate (1.0 g) was dissolved in
tetrahydrofuran:ethanol (1:2) solution (10 mL), and lithium chloride
(0.30 g) and sodium borohydride (0.27 g) were added. The mixture was
stirred at room temperature for 3 hr. The reaction mixture was
partitioned between water and ethyl acetate. The organic layer was washed
with saturated brine and dried over magnesium sulfate. The solvent was
evaporated, and the obtained residue (0.91 g) was reacted and treated in
the same manner as in Example 17 to give
5-hydroxy-N-{[1-(2-hydroxyethyl)pyrazol-4-yl]methyl}-N-(4-isopropylphenyl-
)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.25 g). melting point:
110-114° C.

Example 363

##STR00382##

[1480]By the reaction and treatment in the same manner as in Example 83
using 5-benzyloxy-N-(4-isopropylphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4--
tetrahydronaphthalene-1-carboxamide (1.02 g) and
1-bromo-3-(2-oxanyloxy)propane (0.45 mL) as starting materials,
5-benzyloxy-N-(4-isopropylphenyl)-N-({1-[3-(2-oxanyloxy)propyl]pyrazol-4--
yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.65 g) was
obtained. This compound was dissolved in methanol (30 mL), and 4
mol/L-HCl/dioxane (0.1 mL) was added. The mixture was stirred at room
temperature for 2 hr. Into the reaction mixture was poured saturated
aqueous sodium hydrogencarbonate (2 mL). The reaction mixture was
concentrated under reduced pressure and partitioned between water and
ethyl acetate. The organic layer was washed with saturated brine and
dried over magnesium sulfate. The solvent was evaporated. By the reaction
and treatment of the obtained residue (0.94 g) in the same manner as in
Example 105,
5-hydroxy-N-{[1-(3-hydroxypropyl)pyrazol-4-yl]methyl}-N-(4-isopropylpheny-
l)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.58 g) was obtained.

[1483]By the reaction and treatment in the same manner as in Example 83
using 5-benzyloxy-N-(4-isopropylphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4--
tetrahydronaphthalene-1-carboxamide (0.33 g) and (bromomethyl)cyclohexane
(0.142 mL) as starting materials,
5-benzyloxy-N-{[1-(cyclohexylmethyl)pyrazol-4-yl]methyl}-N-(4-isopropylph-
enyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.26 g) was obtained.
By the reaction and treatment of this compound in the same manner as in
Example 105,
N-{[1-(cyclohexylmethyl)pyrazol-4-yl]methyl}-5-hydroxy-N-(4-isopropylphen-
yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.18 g) was obtained.

[1486]By the reaction and treatment in the same manner as in Example 83
using 5-benzyloxy-N-(4-isopropylphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4--
tetrahydronaphthalene-1-carboxamide (0.37 g) and 3-(chloromethyl)thiophene
(0.21 g) as starting materials,
5-benzyloxy-N-(4-isopropylphenyl)-N-{[1-(3-thienylmethyl)pyrazol-4-yl]met-
hyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.16 g) was obtained. By
the reaction and treatment of this compound (0.11 g), in the same manner
as in Example 133,
5-hydroxy-N-(4-isopropylphenyl)-N-{[1-(3-thienylmethyl)pyrazol-4-yl]methy-
l}-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.054 g) was obtained.

[1489]By the reaction and treatment in the same manner as in Example 82
using 5-benzyloxy-N-(4-methoxyphenyl)-1,2,3,4-tetrahydronaphthalene-1-car-
boxamide (2.98 g) and 1-(tert-butoxycarbonyl)-4-(hydroxymethyl)pyrazole
(1.83 g) as starting materials,
5-benzyloxy-N-(4-methoxyphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahyd-
ronaphthalene-1-carboxamide (1.74 g) was obtained.

[1490]MS (ESI) m/z: 468 [MH].sup.+

Example 367

##STR00386##

[1492]By the reaction and treatment in the same manner as in Example 83
using 5-benzyloxy-N-(4-methoxyphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-te-
trahydronaphthalene-1-carboxamide (0.56 g) and 4-fluorobenzyl chloride
(0.172 mL) as starting materials,
5-benzyloxy-N-{[1-(4-fluorobenzyl)pyrazol-4-yl]methyl}-N-(4-methoxyphenyl-
)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.60 g) was obtained. By
the reaction and treatment of this compound in the same manner as in
Example 133,
N-{[1-(4-fluorobenzyl)pyrazol-4-yl]methyl}-5-hydroxy-N-(4-methoxyphenyl)--
1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.42 g) was obtained.

[1493]melting point: 143-146° C.

Example 368

##STR00387##

[1495]By the reaction and treatment in the same manner as in example 83
using 5-benzyloxy-N-(4-methoxyphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-te-
trahydronaphthalene-1-carboxamide (0.62 g) and ethyl iodide (0.13 mL) as
starting materials,
5-benzyloxy-N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-methoxyphenyl)-1,2,3,4-t-
etrahydronaphthalene-1-carboxamide (0.55 g) was obtained. By the reaction
and treatment of this compound (0.40 g) in the same manner as in Example
133, N-[(1-ethylpyrazol-4-yl)methyl]-5-hydroxy-N-(4-methoxyphenyl)-1,2,3,-
4-tetrahydronaphthalene-1-carboxamide (0.30 g) was obtained. melting
point: 211-213° C.

Example 369

##STR00388##

[1497]By the reaction and treatment in the same manner as in Example 83
using 5-benzyloxy-N-(4-methoxyphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-te-
trahydronaphthalene-1-carboxamide (0.56 g) and (bromomethyl)cyclohexane
(0.20 mL) as starting materials,
5-benzyloxy-N-{[1-(cyclohexylmethyl)pyrazol-4-yl]methyl}-N-(4-methoxyphen-
yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.55 g) was obtained. By
the reaction and treatment in the same manner as in Example 133 using
this compound (0.45 g),
N-{[1-(cyclohexylmethyl)pyrazol-4-yl]methyl}-5-hydroxy-N-(4-methoxyphenyl-
)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.36 g) was obtained.

[1500]By the reaction and treatment in the same manner as in Example 271
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,-
2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.77 g) and
4-(chloromethyl)pyridine (0.49 g) as starting materials,
5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(4-pyridylmethyl)pyrazol-4--
yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.67 g) was
obtained. By the reaction and treatment of this compound in the same
manner as in Example 139,
5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(4-pyridylmethyl)pyrazol-4-yl-
]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide dihydrochloride (0.58
g) was obtained.

[1504]By the reaction and treatment in the same manner as in Example 271
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,-
2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.77 g) and
1-(2-chloroethyl)piperidine hydrochloride (0.55 g) as starting materials,
5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(2-piperidinoethyl)pyrazol--
4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.76 g) was
obtained. By the reaction and treatment of this compound in the same
manner as in Example 139,
5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(2-piperidinoethyl)pyrazol-4--
yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide dihydrochloride
(0.54 g) was obtained.

[1508]By the reaction and treatment in the same manner as in Example 83
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,-
2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.72 g) and
(bromomethyl)cyclohexane (0.25 mL) as starting materials,
5-benzyloxy-N-{[1-(cyclohexylmethyl)pyrazol-4-yl]methyl}-N-(6-isopropylpy-
ridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.86 g) was
obtained. By the reaction and treatment of this compound in the same
manner as in Example 139,
N-{[1-(cyclohexylmethyl)pyrazol-4-yl]methyl}-5-hydroxy-N-(6-isopropylpyri-
din-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.63
g) was obtained.

[1512]By the reaction and treatment in the same manner as in Example 83
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,-
2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.72 g) and
1-bromoheptane (0.283 mL) as starting materials,
5-benzyloxy-N-[(1-heptylpyrazol-4-yl)methyl]-N-(6-isopropylpyridin-3-yl)--
1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.86 g) was obtained. By the
reaction and treatment of this compound in the same manner as in Example
139, N-[(1-heptylpyrazol-4-yl)methyl]-5-hydroxy-N-(6-isopropylpyridin-3-y-
l)-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.62 g) was
obtained.

[1516]By the reaction and treatment in the same manner as in Example 83
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,-
2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.72 g) and
3-chloromethyl-5,6-dihydroimidazo[2,1-b]thiazole hydrochloride (0.38 g)
as starting materials,
5-benzyloxy-N-({1-[(5,6-dihydroimidazo[2,1-b]thiazol-3-yl)methyl]pyrazol--
4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-c-
arboxamide (0.92 g) was obtained. By the reaction and treatment of this
compound in the same manner as in Example 139,
N-({1-[(5,6-dihydroimidazo[2,1-b]thiazol-3-yl)methyl]pyrazol-4-yl}methyl)-
-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-car-
boxamide dihydrochloride (0.50 g) was obtained.

[1520]By the reaction and treatment in the same manner as in Example 83
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,-
2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.72 g) and
(bromomethyl)cyclopropane (0.174 mL) as starting materials,
5-benzyloxy-N-{[1-(cyclopropylmethyl)pyrazol-4-yl]methyl}-N-(6-isopropylp-
yridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.80 g) was
obtained. By the reaction and treatment of this compound in the same
manner as in Example 139,
N-{[1-(cyclopropylmethyl)pyrazol-4-yl]methyl}-5-hydroxy-N-(6-isopropylpyr-
idin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.58
g) was obtained.

[1524]By the reaction and treatment in the same manner as in Example 83
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,-
2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.72 g) and
4-(2-chloroethyl)morpholine hydrochloride (0.33 g) as starting materials,
5-benzyloxy-N-{[1-(2-morpholinoethyl)pyrazol-4-yl]methyl}-N-(6-isopropylp-
yridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.69 g) was
obtained. By the reaction and treatment of this compound in the same
manner as in Example 139,
5-hydroxy-N-{[1-(2-morpholinoethyl)pyrazol-4-yl]methyl}-N-(6-isopropylpyr-
idin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.34
g) was obtained.

[1528]To a solution of
5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4--
tetrahydronaphthalene-1-carboxamide hydrochloride (0.72 g) in
dimethylformamide (5 mL) were added triethylamine (0.23 mL) and
cyclohexanecarbonyl chloride (0.22 mL), and the mixture was stirred at
room temperature for one day. The reaction mixture was partitioned
between water and ethyl acetate. The organic layer was washed with
saturated brine and dried over magnesium sulfate. The solvent was
evaporated, and the residue was purified by silica gel column
chromatography to give
5-benzyloxy-N-{[1-(cyclohexylcarbonyl)pyrazol-4-yl]methyl}-N-(6-isopropyl-
pyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.67 g). By the
reaction and treatment of this compound in the same manner as in Example
139, N-{[1-(cyclohexanecarbonyl)pyrazol-4-yl]methyl}-5-hydroxy-N-(6-isopr-
opylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide
hydrochloride (0.23 g) was obtained.

[1532]By the reaction and treatment in the same manner as in Example 271
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,-
2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.83 g) and
3-(chloromethyl)thiophene (0.27 g) as starting materials,
5-benzyloxy-N-{[1-(3-thienylmethyl)pyrazol-4-yl]methyl}-N-(6-isopropylpyr-
idin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.48 g) was
obtained. By the reaction and treatment of this compound in the same
manner as in Example 139,
5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(3-thienylmethyl)pyrazol-4-yl-
]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.39
g) was obtained.

[1536]By the reaction and treatment in the same manner as in Example 271
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,-
2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.83 g) and
4-(chloromethyl)-2-methylthiazole (0.55 g) as starting materials,
5-benzyloxy-N-({1-[(2-methylthiazol-4-yl)methyl]pyrazol-4-yl}methyl)-N-(6-
-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.73
g) was obtained. By the reaction and treatment of this compound in the
same manner as in Example 139,
5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(2-methylthiazol-4-yl)methyl-
]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide
hydrochloride (0.62 g) was obtained.

[1540]By the reaction and treatment in the same manner as in Example 271
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,-
2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.83 g) and
1-bromobutane (0.322 mL) as starting materials,
5-benzyloxy-N-[(1-butylpyrazol-4-yl)methyl]-N-(6-isopropylpyridin-3-yl)-1-
,2,3,4-tetrahydronaphthalene-1-carboxamide (0.66 g) was obtained. By the
reaction and treatment of this compound in the same manner as in Example
139, N-[(1-butylpyrazol-4-yl)methyl]-5-hydroxy-N-(6-isopropylpyridin-3-yl-
)-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.41 g) was
obtained. MS (ESI) m/z: 447 [MH]+

[1543]By the reaction and treatment in the same manner as in Example 271
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,-
2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.83 g) and
isobutyl bromide (0.326 mL) as starting materials,
5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(2-methylpropyl)pyrazol-4-y-
l]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.16 g) was
obtained. By the reaction and treatment of this compound in the same
manner as in Example 19,
5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(2-methylpropyl)pyrazol-4-yl]-
methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.11 g)
was obtained.

[1547]By the reaction and treatment in the same manner as in Example 271
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,-
2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.83 g) and
1-bromo-3-methylbutane (0.359 mL) as starting materials,
5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(3-methylbutyl)pyrazol-4-yl-
]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.60 g) was
obtained. By the reaction and treatment of this compound in the same
manner as in Example 139,
5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(3-methylbutyl)pyrazol-4-yl]m-
ethyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.45 g)
was obtained.

[1554]By the reaction and treatment in the same manner as in Example 83
using 5-benzyloxy-N-(6-methoxypyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,-
3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.94 g) and benzyl
bromide (0.285 mL) as starting materials,
5-benzyloxy-N-[(1-benzylpyrazol-4-yl)methyl]-N-(6-methoxypyridin-3-yl)-1,-
2,3,4-tetrahydronaphthalene-1-carboxamide (0.31 g) was obtained. By the
reaction and treatment of this compound in the same manner as in Example
139, N-[(1-benzylpyrazol-4-yl)methyl]-5-hydroxy-N-(6-methoxypyridin-3-yl)-
-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.087 g) was
obtained.

[1558]By the reaction and treatment in the same manner as in Example 83
using 5-benzyloxy-N-(6-methoxypyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,-
3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.94 g) and
2-(chloromethyl)pyridine hydrochloride (0.33 g) as starting materials,
5-benzyloxy-N-(6-methoxypyridin-3-yl)-N-{[1-(2-pyridylmethyl)pyrazol-4-yl-
]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.28 g) was
obtained. By the reaction and treatment of this compound in the same
manner as in Example 139,
5-hydroxy-N-(6-methoxypyridin-3-yl)-N-{[1-(2-pyridylmethyl)pyrazol-4-yl]m-
ethyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide dihydrochloride (0.085
g) was obtained.

[1562]By the reaction and treatment in the same manner as in Example 271
using 5-benzyloxy-N-[(pyrazol-4-yl)methyl]-N-(6-methoxypyridin-3-yl)-1,2,-
3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.936 g) and
4-(trifluoromethyl)benzyl chloride (0.592 mL) as starting materials,
5-benzyloxy-N-(6-methoxypyridin-3-yl)-N-{[1-(4-trifluoromethylbenzyl)pyra-
zol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.25 g) was
obtained. By the reaction and treatment of this compound in the same
manner as in Example 133,
5-hydroxy-N-(6-methoxypyridin-3-yl)-N-{[1-(4-trifluoromethylbenzyl)pyrazo-
l-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.53 g) was
obtained. melting point: 199-200° C.

Example 387

##STR00406##

[1564]By the reaction and treatment in the same manner as in Example 271
using 5-benzyloxy-N-[(pyrazol-4-yl)methyl]-N-(6-methoxypyridin-3-yl)-1,2,-
3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.70 g) and
2-(2-chloroethyl)pyridine (0.42 g) as starting materials,
5-benzyloxy-N-(6-methoxypyridin-3-yl)-N-({1-[2-(2-pyridyl)ethyl]pyrazol-4-
-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.45 g) was
obtained. By the reaction and treatment of this compound in the same
manner as in Example 139,
5-hydroxy-N-(6-methoxypyridin-3-yl)-N-({1-[2-(2-pyridyl)ethyl]pyrazol-4-y-
l}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide dihydrochloride
(0.31 g) was obtained.

[1568]By the reaction and treatment in the same manner as in Example 271
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,-
2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.83 g) and
2-(2-chloroethyl)pyridine (0.42 g) as starting materials,
5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[2-(2-pyridyl)ethyl]pyrazol-
-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.56 g) was
obtained. By the reaction and treatment of this compound in the same
manner as in Example 139,
5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-({1-[2-(2-pyridyl)ethyl]pyrazol-4-
-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide dihydrochloride
(0.41 g) was obtained.

[1572]By the reaction and treatment in the same manner as in Example 83
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,-
2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.96 g) and
dodecyl bromide (0.719 mL) as starting materials,
5-benzyloxy-N-[(1-dodecylpyrazol-4-yl)methyl]-N-(6-isopropylpyridin-3-yl)-
-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.29 g) was obtained. By the
reaction and treatment of this compound in the same manner as in Example
139, N-[(1-dodecylpyrazol-4-yl)methyl]-5-hydroxy-N-(6-isopropylpyridin-3--
yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.54 g) was
obtained. MS (ESI) m/z: 559 [MH]+

[1575]By the reaction and treatment in the same manner as in Example 83
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,-
2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.96 g) and nonyl
bromide (0.57 mL) as starting materials,
5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(1-nonylpyrazol-4-yl)methyl]-1-
,2,3,4-tetrahydronaphthalene-1-carboxamide (1.20 g) was obtained. By the
reaction and treatment of this compound in the same manner as in Example
139, 5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-[(1-nonylpyrazol-4-yl)methyl-
]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.81 g) was
obtained.

[1579]By the reaction and treatment in the same manner as in Example 83
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,-
2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (3.26 g) and ethyl
7-bromoheptanoate (2.0 mL) as starting materials, ethyl
7-(4-{[N-(5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-ylcarbonyl)-N-(6-iso-
propylpyridin-3-yl)amino]methyl}pyrazol-1-yl)heptanoate (4.25 g) was
obtained.

[1580]MS (ESI) m/z: 637 [MH].sup.+

Example 392

##STR00411##

[1582]Ethyl
7-(4-{[N-(5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-ylcarbonyl)-N-(6-iso-
propylpyridin-3-yl)amino]methyl}pyrazol-1-yl)heptanoate (2.0 g) was
dissolved in ethanol (100 mL), and 1 mol/L-aqueous sodium hydroxide
solution (6.60 mL) was added. The mixture was stirred at room temperature
for 1 hr. To the reaction mixture was added 1 mol/L-hydrochloric acid
(6.60 mL), and the mixture was extracted with ethyl acetate. The organic
layer was washed with saturated brine and dried over anhydrous magnesium
sulfate. The solvent was evaporated, and the residue was purified by
silica gel column chromatography to give
7-(4-{[N-(5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-ylcarbonyl)-N-(6-iso-
propylpyridin-3-yl)amino]methyl}pyrazol-1-yl)heptanoic acid (1.80 g). By
the reaction and treatment of this compound in the same manner as in
Example 139,
7-(4-{[N-(5-hydroxy-1,2,3,4-tetrahydronaphthalen-1-ylcarbonyl)-N-(6-isopr-
opylpyridin-3-yl)amino]methyl}pyrazol-1-yl)heptanoic acid hydrochloride
(0.84 g) was obtained.

[1586]By the reaction and treatment in the same manner as in Example 256
using ethyl
7-(4-{[N-(5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-ylcarbonyl)-N-(6-iso-
propylpyridin-3-yl)amino]methyl}pyrazol-1-yl)heptanoate (2.2 g) as a
starting material,
5-benzyloxy-N-{[1-(7-hydroxyheptyl)pyrazol-4-yl]methyl}-N-(6-isopropylpyr-
idin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.30 g) was
obtained. By the reaction and treatment of this compound in the same
manner as in Example 139,
5-hydroxy-N-{[1-(7-hydroxyheptyl)pyrazol-4-yl]methyl}-N-(6-isopropylpyrid-
in-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.48
g) was obtained.

[1590]To a solution of ethylene glycol monobutyl ether (1 mL) and
triethylamine (1.6 mL) in dichloromethane (20 mL) was added
methanesulfonyl chloride (0.88 mL) under ice-cooling, and the mixture was
stirred at room temperature for one day. The reaction mixture was
partitioned between water and chloroform, washed with saturated brine and
dried over magnesium sulfate. The solvent was evaporated, and the
obtained residue and
5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4--
tetrahydronaphthalene-1-carboxamide hydrochloride (1.0 g) were reacted and
treated in the same manner as in Example 83 to give
5-benzyloxy-N-{[1-(2-butoxyethyl)pyrazol-4-yl]methyl}-N-(6-isopropylpyrid-
in-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.58 g).

[1591]MS (ESI) m/z: 581 [MH].sup.+

Example 395

##STR00414##

[1593]By the reaction and treatment in the same manner as in Example 139
using 5-benzyloxy-N-{[1-(2-butoxyethyl)pyrazol-4-yl]methyl}-N-(6-isopropy-
lpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.58 g) as a
starting material,
N-{[1-(2-butoxyethyl)pyrazol-4-yl]methyl}-5-hydroxy-N-(6-isopropylpyridin-
-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.25 g)
was obtained.

[1597]By the reaction and treatment in the same manner as in Example 394
using diethylene glycol monomethyl ether (1 mL) and
5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4--
tetrahydronaphthalene-1-carboxamide (1.0 g) as starting materials,
5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[2-(2-methoxyethoxy)ethyl]p-
yrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.76 g)
was obtained.

[1598]MS (ESI) m/z: 583 [MH]+

Example 397

##STR00416##

[1600]By the reaction and treatment in the same manner as in Example 139
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[2-(2-methoxyethoxy)e-
thyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide
(0.76 g) as a starting material,
5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-({1-[2-(2-methoxyethoxy)ethyl]pyr-
azol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide
hydrochloride (0.20 g) was obtained.

[1604]By the reaction and treatment in the same manner as in Example 12
using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.56
g) and (4-isopropylphenyl)[(6-morpholinopyridin-3-yl)methyl]amine (0.62
g) as starting materials,
5-benzyloxy-N-(4-isopropylphenyl)-N-[(6-morpholinopyridin-3-yl)methyl]-1,-
2,3,4-tetrahydronaphthalene-1-carboxamide (0.90 g) was obtained.

[1607]By the reaction and treatment in the same manner as in Example 105
using 5-benzyloxy-N-(4-isopropylphenyl)-N-[(6-morpholinopyridin-3-yl)meth-
yl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.88 g) as a starting
material, 5-hydroxy-N-(4-isopropylphenyl)-N-[(6-morpholinopyridin-3-yl)me-
thyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.51 g) was obtained.

[1610]By the reaction and treatment in the same manner as in Example 12
using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.56
g) and (4-isopropylphenyl)([6-(2-methoxyethoxy)pyridin-3-yl]methyl)amine
(0.60 g) as starting materials,
5-benzyloxy-N-(4-isopropylphenyl)-N-([6-(2-methoxyethoxy)pyridin-3-yl]met-
hyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.52 g) was obtained.

[1613]By the reaction and treatment in the same manner as in Example 17
using 5-benzyloxy-N-(4-isopropylphenyl)-N-{[6-(2-methoxyethoxy)pyridin-3--
yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.88 g) as a
starting material,
5-hydroxy-N-(4-isopropylphenyl)-N-{[6-(2-methoxyethoxy)pyridin-3-yl]methy-
l}-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.35 g) was obtained.
melting point: 153° C.

Example 402

##STR00421##

[1615]To a solution of
N-({1-[(4-fluorophenyl)methyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(6-isoprop-
ylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.55 g) in
chloroform (10 mL) was added m-chloroperbenzoic acid (0.29 g), and the
mixture was stirred at room temperature for 2 hr. The reaction mixture
was partitioned between water and chloroform. The organic layer was
washed with saturated brine and dried over anhydrous magnesium sulfate.
The solvent was evaporated and the residue was purified by silica gel
column chromatography to give
N-({1-[(4-fluorophenyl)methyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(6-isoprop-
yl-1-oxidopyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide
hydrochloride (0.13 g).

[1619]By the reaction and treatment in the same manner as in Example 271
using 5-benzyloxy-N-(4-isopropylphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4--
tetrahydronaphthalene-1-carboxamide (0.62 g) and
2-(chloromethyl)-4-methylpyridine hydrochloride (0.46 g) as starting
materials,
5-benzyloxy-N-(4-isopropylphenyl)-N-({1-[(4-methylpyridin-2-yl)methyl]pyr-
azol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.53 g) was
obtained.

[1622]By the reaction and treatment in the same manner as in Example 133
using 5-benzyloxy-N-(4-isopropylphenyl)-N-({1-[(4-methylpyridin-2-yl)meth-
yl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.53
g) as a starting material,
5-hydroxy-N-(4-isopropylphenyl)-N-({1-[(4-methylpyridin-2-yl)methyl]pyraz-
ol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.50 g) was
obtained.

[1625]By the reaction and treatment in the same manner as in Example 402
using 5-hydroxy-N-(4-isopropylphenyl)-N-({1-[4-methylpyridin-2-yl]methyl}-
pyrazol-4-yl)methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.50 g)
as a starting material,
5-hydroxy-N-(4-isopropylphenyl)-N-({1-[(4-methyl-1-oxidopyridin-2-yl)meth-
yl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.16
g) was obtained.

[1628]By the reaction and treatment in the same manner as in Example 271
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,-
2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and
5-chloromethyl-2-ethoxypyridine (0.51 g) as starting materials,
5-benzyloxy-N-({1-[(6-ethoxypyridin-3-yl)methyl]pyrazol-4-yl}methyl)-N-(6-
-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.67
g) was obtained.

[1631]By the reaction and treatment in the same manner as in Example 101
using 5-benzyloxy-N-({1-[(6-ethoxypyridin-3-yl)methyl]pyrazol-4-yl}methyl-
)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide
(0.66 g) as a starting material,
N-({1-[(6-ethoxypyridin-3-yl)methyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(6-i-
sopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide
dihydrochloride (0.54 g) was obtained.

[1632]MS (ESI) m/z: 526 [MH].sup.+

Example 408

##STR00427##

[1634]By the reaction and treatment in the same manner as in Example 271
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,-
2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.65 g) and
6-chloromethyl-2-morpholinopyridine (0.29 g) as starting materials,
5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(6-morpholinopyridin-2-yl)-
methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide
(0.44 g) was obtained.

[1640]By the reaction and treatment in the same manner as in Example, 271
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,-
2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and
5-chloromethyl-2-(2-methoxyethoxy)pyridine (0.61 g) as starting
materials,
5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(1-{[6-(2-methoxyethoxy)pyridi-
n-3-yl]methyl}pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxa-
mide (0.77 g) was obtained.

[1643]By the reaction and treatment in the same manner as in Example 101
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(1-{[6-(2-methoxyethoxy)-
pyridin-3-yl]methyl}pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-c-
arboxamide (0.76 g) as a starting material,
5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-[(1-{[6-(2-methoxyethoxy)pyridin--
3-yl]methyl}pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxami-
de dihydrochloride (0.55 g) was obtained.

[1647]By the reaction and treatment in the same manner as in Example 271
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,-
2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and
6-chloromethyl-2-methoxypyridine (0.47 g) as starting materials,
5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(6-methoxypyridin-2-yl)met-
hyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.44
g) was obtained.

[1650]By the reaction and treatment in the same manner as in Example 101
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(6-methoxypyridin-2--
yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide
(0.43 g) as a starting material,
5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-(({1-[(6-methoxypyridin-2-yl)meth-
yl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide
dihydrochloride (0.34 g) was obtained. MS (ESI) m/z: 512 [MH]+

[1653]By the reaction and treatment in the same manner as in Example 83
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,-
2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and
isopropyl iodide (0.30 mL) as starting materials,
5-benzyloxy-N-[(1-isopropylpyrazol-4-yl)methyl]-N-(6-isopropylpyridin-3-y-
l)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.68 g) was obtained.

[1656]By the reaction and treatment in the same manner as in Example 101
using 5-benzyloxy-N-[(1-isopropylpyrazol-4-yl)methyl]-N-(6-isopropylpyrid-
in-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.67 g) as a
starting material,
5-hydroxy-N-[(1-isopropylpyrazol-4-yl)methyl]-N-(6-isopropylpyridin-3-yl)-
-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.52 g) was obtained.

[1660]By the reaction and treatment in the same manner as in Example 12
using 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.41 g)
and [(4-dimethylaminophenyl)methyl](6-isopropylpyridin-3-yl)amine (0.54
g) as starting materials,
N-[(4-dimethylaminophenyl)methyl]-N-(6-isopropylpyridin-3-yl)-7-methoxy-1-
,2,3,4-tetrahydronaphthalene-1-carboxamide (0.13 g) was obtained.

[1664]By the reaction and treatment in the same manner as in Example 83
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,-
2,3,4-tetrahydronaphthalene-1-carboxamide (0.96 g) and
2-(chloromethyl)thiophene (0.25 g) as a starting material,
5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(2-thienylmethyl)pyrazol-4--
yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.95 g) was
obtained. By the reaction and treatment of this compound in the same
manner as in Example 133,
5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(2-thienylmethyl)pyrazol-4-yl-
]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.41 g) was
obtained. melting point: 125-129° C.

Example 418

##STR00437##

[1666]By the reaction and treatment in the same manner as in Example 83
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,-
2,3,4-tetrahydronaphthalene-1-carboxamide (1.44 g) and
2-chloro-5-(chloromethyl)thiophene (0.79 g) as starting materials,
5-benzyloxy-N-({1-[(5-chlorothiophen-2-yl)methyl]pyrazol-4-yl}methyl)-N-(-
6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.37
g) was obtained. By the reaction and treatment of this compound in the
same manner as in Example 133,
N-({1-[(5-chlorothiophen-2-yl)methyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(6--
isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.37
g) was obtained. melting point: 98-101° C.

Example 419

##STR00438##

[1668]By the reaction and treatment of diethylene glycol monobutyl ether
(1.0 mL) and
5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4--
tetrahydronaphthalene-1-carboxamide (0.96 g) in the same manner as in
Example 394,
5-benzyloxy-N-({1-[2-(2-butoxyethoxy)ethyl]pyrazol-4-yl}methyl)-N-(6-isop-
ropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.94 g)
was obtained.

[1669]MS (ESI) m/z: 625 [MH].sup.+

Example 420

##STR00439##

[1671]By the reaction and treatment in the same manner as in Example 139
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[2-(2-butoxyethoxy)et-
hyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.94
g) as a starting material,
N-({1-[2-(2-butoxyethoxy)ethyl]pyrazol-4-yl}methyl)-5-hydroxy-N-(6-isopro-
pylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride
(0.48 g) was obtained.

[1675]By the reaction and treatment of diethylene glycol monoethyl ether
(1.5 mL) and
5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4--
tetrahydronaphthalene-1-carboxamide (0.72 g) in the same manner as in
Example 394,
5-benzyloxy-N-({1-[2-(2-methoxyethoxy)ethyl]pyrazol-4-yl}methyl)-N-(6-iso-
propylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.89 g)
was obtained.

[1676]MS (ESI) m/z: 597 [MH].sup.+

Example 422

##STR00441##

[1678]By the reaction and treatment in the same manner as in Example 139
using 5-benzyloxy-N-({1-[2-(2-methoxyethoxy)ethyl]pyrazol-4-yl}methyl)-N--
(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide
(0.00 g) as a starting material,
5-hydroxy-N-({1-[2-(2-methoxyethoxy)ethyl]pyrazol-4-yl}methyl)-N-(6-isopr-
opylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide
hydrochloride (0.15 g) was obtained.

[1682]By the reaction and treatment in the same manner as in Example 12
using 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.64 g)
and (4-isopropylphenyl){[4-(2,2,2-trifluoroethoxy)phenyl]methyl}amine
(1.0 g) as starting materials,
N-(4-isopropylphenyl)-7-methoxy-N-{[4-(2,2,2-trifluoroethoxy)phenyl]methy-
l}-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.58 g) was obtained.
melting point: 125-127° C.

Example 424

##STR00443##

[1684]By the reaction and treatment in the same manner as in Example 271
using 5-benzyloxy-N-(6-methoxypyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,-
3,4-tetrahydronaphthalene-1-carboxamide (0.94 g) and
2-chloromethyl-4-methylpyridine hydrochloride (0.71 g) as starting
materials,
5-benzyloxy-N-(6-methoxypyridin-3-yl)-N-({1-[(4-methylpyridin-2-yl)methyl-
]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.90 g)
was obtained.

[1687]By the reaction and treatment in the same manner as in Example 101
using 5-benzyloxy-N-(6-methoxypyridin-3-yl)-N-({1-[(4-methylpyridin-2-yl)-
methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide
(0.90 g) as a starting material,
5-hydroxy-N-(6-methoxypyridin-3-yl)-N-({1-[(4-methylpyridin-2-yl)methyl]p-
yrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide
dihydrochloride (0.67 g) was obtained. MS (ESI) m/z: 484 [MH]+

[1690]By the reaction and treatment in the same manner as in Example 271
using 5-benzyloxy-N-(6-methoxypyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,-
3,4-tetrahydronaphthalene-1-carboxamide (0.94 g) and
2-chloromethyl-5-methylpyridine hydrochloride (0.71 g) as starting
materials,
5-benzyloxy-N-(6-methoxypyridin-3-yl)-N-({1-[(5-methylpyridin-2-yl)methyl-
]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.94 g)
was obtained.

[1693]By the reaction and treatment in the same manner as in Example 101
using 5-benzyloxy-N-(6-methoxypyridin-3-yl)-N-({1-[(5-methylpyridin-2-yl)-
methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide
(0.94 g) as a starting material,
5-hydroxy-N-(6-methoxypyridin-3-yl)-N-({1-[(5-methylpyridin-2-yl)methyl]p-
yrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide
dihydrochloride (0.73 g) was obtained. MS (ESI) m/z: 484 [MH]+

[1701]By the reaction and treatment in the same manner as in Example 132
using 5-benzyloxy-N-(5-methylpyridin-2-yl)-1,2,3,4-tetrahydronaphthalene--
1-carboxamide (1.43 g) and 5-chloromethyl-2-ethyl-4-methylthiazole (0.68
g) as starting materials,
5-benzyloxy-N-[(2-ethyl-4-methylthiazol-5-yl)methyl]-N-(5-methylpyridin-2-
-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.92 g) was obtained.

[1704]By the reaction and treatment in the same manner as in Example 101
using 5-benzyloxy-N-[(2-ethyl-4-methylthiazol-5-yl)methyl]-N-(5-methylpyr-
idin-2-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.92 g) as a
starting material,
N-[(2-ethyl-4-methylthiazol-5-yl)methyl]-5-hydroxy-N-(5-methylpyridin-2-y-
l)-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.57 g) was
obtained. MS (ESI) m/z: 422 [MH]+

[1707]By the reaction and treatment in the same manner as in Example 142
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthale-
ne-1-carboxamide (0.53 g) and 2-(2-butoxyethoxy)-5-(hydroxymethyl)pyridine
(0.30 g) as starting materials,
5-benzyloxy-N-{[6-(2-butoxyethoxy)pyridin-3-yl]methyl}-N-(6-isopropylpyri-
din-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.40 g) was
obtained.

[1708]MS (ESI) m/z: 608 [MH].sup.+

Example 433

##STR00452##

[1710]By the reaction and treatment in the same manner as in Example 139
using 5-benzyloxy-N-{[6-(2-butoxyethoxy)pyridin-3-yl]methyl}-N-(6-isoprop-
ylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.40 g) as a
starting material,
N-{[6-(2-butoxyethoxy)pyridin-3-yl]methyl}-5-hydroxy-N-(6-isopropylpyridi-
n-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.10 g) was obtained.
MS (ESI) m/z: 518 [MH]+

[1713]By the reaction and treatment in the same manner as in Example 132
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthale-
ne-1-carboxamide (2.05 g) and
4-chloromethyl-1-(2,2,2-trifluoroethyl)pyrazole (1.02 g) as starting
materials,
5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(2,2,2-trifluoroethyl)pyraz-
ol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.70 g) was
obtained.

[1717]By the reaction and treatment in the same manner as in Example 17
using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(2,2,2-trifluoroethyl-
)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.81 g)
as a starting material,
5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(2,2,2-trifluoroethyl)pyrazol-
-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.23 g) was
obtained. melting point: 127.7° C.

[1726]The superior pharmacological effect of the compound of the formula
(1) is verified by a series of the following tests.

Test Example 1

C5a Receptor Binding Assay

[1727]The C5a receptor binding inhibitory action of C5a and the test
compound was evaluated by a receptor binding assay comprising reacting
human cell line U-937 (human histiocytic lymphoma line), which expresses
the C5a receptor, with [125I]-human C5a (Amersham Pharmacia Biotech)
in a MultiScreen (MILLIPORE). First, U-937 cell was stimulated with 1 mM
dibutyryl cyclic AMP (dcAMP, SIGMA) for 2 days to express the C5a
receptor (dcAMP-U937 cell), and suspended in a binding buffer [50 mM
HEPES, 1 mM CaCl2, 5 mM MgCl2, 0.5% bovine albumin (BSA,
SIGMA), 0.02% NaN3 (pH 7.2)] and stored at -80° C. The
binding assay was started by the addition of 1×105 cells/50
μL of dcAMP-U937 cell suspension dissolved immediately before use, 25
μL of a test compound solution (obtained by dissolving the test
compound in N,N-Dimethylformamide to a final concentration of 10 mmol/L
and diluting with binding buffer), and 25 μL of [125I]-C5a
solution (final concentration 200 pM), to each well of the MultiScreen.
For calculation of non-specific binding, wells containing a non-labeled
C5a (final concentration 20 nM) or binding buffer instead of the test
compound were prepared. After incubation at 4° C. for 2 hr,
suction filtration and addition of 300 μL of the binding buffer were
repeated 4 times to remove non-binding portion. After drying the
MultiScreen, the radioactivity on the filter was measured using a gamma
counter.

[1728]The rate (% inhibition) of inhibition of C5a binding by the test
compound was calculated by the following formula using the count value
obtained without addition of the test compound as Total, the count value
obtained with addition of non-labeled C5a as Non, and the count value
obtained with addition of the test compound as Test.

% Inhibition=100-[(Test-Non)/(Total-Non)]×100

[1729]Further, the concentration (IC50 value) of the test compound,
at which binding of [125I]-human C5a is inhibited by 50%, was
calculated by two-interpolation method. In this evaluation system,
IC50 value of the compound of Example 4 was 104 nmol/L.

[1730]A neutrophil fraction was separately taken from human peripheral
venous blood using Lympholyte-poly (Cedarlane), and suspended in Hank's
Balanced Salt Solution (HBSS, GIBCO BRL) supplemented with 1% fetal
bovine serum (FBS). Then, Fura 2-AM (final concentration 5 μM,
DOJINDO) was added to the neutrophil fraction (5×106
cells/mL), and the mixture was incubated at 37° C. for 40 min. The
cells were washed by centrifugation and suspended to the concentration of
1×106 cells/mL. The intracellular Ca2+ concentration was
measured using a spectrophotofluorometer (CAF-110, JASCO Corporation),
and calculated from the ratio (Ex340 value/Ex380 value) of fluorescent
intensities at 500 nm upon excitation at 340 nm and 380 nm, the former
being Ex340 value, the latter being Ex380 value. To be specific, a
neutrophil suspension (450 μL, 1×106 cells/mL) was
dispensed to a cuvette having a stirrer bar at 5 min before the
measurement and the suspension was heated to 37° C. Then the
cuvette was set on CAF-110 set for 37° C., and the measurement was
started. Immediately thereafter, 50 μL of a test compound solution was
added. About 45 sec later, 5 μL of recombinant human C5a (final
concentration 100 pmol/L) was added and the measurement was continued for
about 1 min. Then, Triton X-100 (final concentration 0.2%) was added and
the cells were dissolved, and sb2 value, which was the Ex340 value then,
and Rmax value, which was the Ex340 value/Ex380 value then, was measured.
Then, EGTA (final concentration 3 mmol/L) was added and sf2 value, which
was the Ex340 value then, and Rmin value, which was the Ex340/Ex380 value
then, was measured. From these measurement results, the intracellular
Ca2+ concentration was calculated from the following formula.

[1731]In the formula, the Ex340 value/Ex380 value is the value at each
continuous point over the entire period of measurement.

[1732]The rate (% inhibition) of the inhibition of increase in
intracellular Ca2+ concentration of C5a stimulated neutrophil by the
test compound was calculated by the following formula, wherein the peak
value of increase in intracellular Ca2+ concentration derived by C5a
without addition of the test compound is Max, the peak value of
intracellular Ca2+ concentration without addition of the test
compound and without stimulation with C5a is Min, and the peak value of
increase in intracellular Ca2+ concentration derived by C5a with the
addition of the test compound is Test.

% Inhibition=100-[(Test-Min)/(Max-Min)]×100

[1733]Further, the concentration (IC50 value) of the test compound,
at which increase in intracellular Ca2+ concentration of
C5a-stimulated neutrophil is inhibited by 50%, was calculated by
two-interpolation method.

[1734]The IC50 value of the compound of Example 4 was 5 nmol/L.
Moreover, addition of the compound of Example 4 (3 μmol/L) did not
induce an increase in intracellular Ca2+ and the agonistic action
was not found.

Test Example 3

Action of C5a-Stimulated Neutrophil on Production of Reactive Oxygen
Species

[1735]A neutrophil fraction was separately taken from human peripheral
venous blood using Lympholyte-poly (Cedarlane), and suspended in Hank's
Balanced Salt Solution (HBSS, GIBCO BRL) containing 1% fetal bovine serum
(FBS) and 1 mmol/L of luminol (Wako Pure Chemical Industries, Ltd.).
Reactive oxygen species was measured using a luminometer (MicroLumat,
Berthold) for 96 well plate. That is, 1×105 cells/150 μL of
neutrophil suspension and 25 μL of a test compound solution (obtained
by dissolving the test compound in N,N-Dimethyl formamide to a final
concentration of 10 mmol/L and diluting with HBSS supplemented with 1%
FBS) were added to a well, which was set in a MicroLumat set for
37° C. and stood for about 5 min. Then, 25 μL of C5a (final
concentration 3 nmol/L) was added and luminescence produced by the
reaction of the luminol and the reactive oxygen species was measured with
the lapse of time for 15 min. The rate (% inhibition) of inhibition of
the production of reactive oxygen species in C5a stimulated neutrophil by
the test compound was calculated by the following formula, wherein the
peak value of the production of reactive oxygen species derived by C5a
without addition of the test compound is Max, the peak value of the
production of reactive oxygen species without addition of the test
compound and without C5a stimulation is Min, and the peak value of the
production of reactive oxygen species derived by C5a with the addition of
the test compound is Test.

% Inhibition=100-[(Test-Min)/(Max-Min)]×100

[1736]In addition, the concentration (IC50 value) of the test
compound, at which the production of reactive oxygen species in C5a
stimulated neutrophil is inhibited by 50%, was calculated by
two-interpolation method.

[1737]The IC50 value of the compound of Example 4 was 10 nmol/L.

Test Example 4

Action on Migrating Ability of C5a-Stimulated Neutrophil

[1738]A neutrophil fraction was separately taken from human peripheral
venous blood using Lympholyte-poly (Cedarlane) and suspended in RPMI 1640
medium (GIBCO BRL) supplemented with 0.1% bovine serum albumin (BSA). To.
this neutrophil fraction (5×106 cells/mL) was added Calcein-AM
(final concentration 5 μM, FUNAKOSHI), and the mixture was incubated
at 37° C. for 30 min. The cells were washed by centrifugation and
suspended to a concentration of 1×106 cells/mL. The migration
was evaluated by adding neutrophils to chemotaxicell (pore size: 3 μm,
KURABO) and measuring the neutrophils that migrated outside the
chemotaxicell. First, 100 pmol/L of C5a solution was added to 24 well
plate (500 μL/well) and chemotaxicell was set in the well. Then,
neutrophil suspension and test compound solution (200 μL each) were
added to the inside of the chemotaxicell and incubated at 37° C.,
5% CO2 for 90 min. After the completion of the reaction,
chemotaxicell was removed after shaking well and 100 μL of cell lysate
solution (10% SDS, 0.01 mol/L HCl) was added. The fluorescent intensity
of each well was measured by Cyto Fluor II (Ex: 485, Em: 530). The rate
(% inhibition) of the inhibition of migration of C5a-stimulated
neutrophil by the test compound was calculated by the following formula,
wherein the fluorescence intensity of neutrophil that migrated by C5a
stimulation without addition of the test compound is Max, the fluorescent
intensity of neutrophil that migrated without addition of test compound
and without C5a stimulation is Min, and the fluorescent intensity of
neutrophil that migrated by C5a stimulation with the addition of the test
compound is Test.

% Inhibition=100-[(Test-Min)/(Max-Min)]×100

[1739]Further, the concentration (IC50 value) of the test compound,
at which migration of C5a-stimulated neutrophil is inhibited by 50%, was
calculated by two-interpolation method.

[1740]The IC50 value of the compound of Example 4 was 100 nmol/L.

Test Example 5

Action on C5a Induced Neutrophil Decrease in Monkey

[1741]The test compound is intravenously, subcutaneously or orally
administered to cynomolgus monkey. Then human C5a (SIGMA) is
intravenously administered. The peripheral neutrophil count is taken with
the lapse of time, and suppressive action by the test compound on the
decrease in peripheral neutrophil count is evaluated.

Test Example 6

Action on Collagen-Induced Arthritis in Monkey

[1742]Type II collagen derived from bovine (purchased from Collagen
Research Center) is intradermally inoculated twice to the back of
cynomolgus monkey, together with complete Freund's adjuvant H37Rv
(purchased from Wako Pure Chemical Industries, Ltd.) on the first day of
testing and day 21. The test compound is orally administered from day 22
to day 33 after inoculation. The swelling of four limb joints is observed
according to the scores of 0 (no change)-3 (edema of 5 toes). The joint
swelling score of each monkey is shown by the total scores of four limbs.

Test Example 7

Toxicity Test

[1743]In a single administration toxicity test, the test compound is
administered to male and female SD rats (3 per group) and cynomolgus
monkey (1 per group) and the toxicity by single administration is
evaluated using the presence or absence of death incident, general
condition and body weight as indices. In a repeat administration toxicity
test, the test compound is repeatedly administered to male and female SD
rats (6 per group) and male and female cynomolgus monkeys (2 per group)
for 2 weeks and the toxicity of the test compound by repeat
administration is evaluated using general condition, body weight, diet
intake, hematological test, biochemical test for blood, weight of organs
and autopsy (including pathological test of tissues) as indices.

Test Example 8

Evaluation of Bioavailability in Rat

[1744]The test compound is intravenously and orally administered to male
SD rats (5 per group), and the blood is drawn with the lapse of time.
Using high performance liquid chromatography, the drug concentration in
plasma is measured. The bioavailability (BA) is calculated by the
following formula.

[1745]The compound of the formula (1) of the present invention, an
optically active form thereof and pharmaceutical acceptable salt thereof
have a C5a receptor antagonistic action and are useful as an agent for
the prophylaxis or treatment of diseases or syndromes due to inflammation
caused by C5a [e.g., autoimmune diseases such as rheumatism, systemic
lupus erythematosus and the like, sepsis, adult respiratory distress
syndrome, chronic obstructive pulmonary disease, allergic diseases such
as asthma and the like, atherosclerosis, cardiac infarction, brain
infarction, psoriasis, Alzheimer's disease and serious organ injury
(e.g., pneumonia, nephritis, hepatitis and pancreatitis and the like) due
to activation of leukocytes caused by ischemia reperfusion, trauma, burn,
surgical invasion and the like]. In addition, it is useful as an agent
for the prophylaxis or treatment of infectious diseases caused by
bacteria or virus that invades via a C5a receptor.

[1746]This application is based on a patent application Nos. 280540/2000
and 386813/2000 filed in Japan, the contents of which are hereby
incorporated by reference.